ORCID Profile
0000-0003-3644-7093
Current Organisations
Universitas Sebelas Maret
,
Pukyong National University
,
The Alfred Hospital
,
Monash University
,
University of Queensland
,
Alfred Health
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Gene Expression | Genetics | Developmental Genetics (incl. Sex Determination) | Epigenetics (incl. Genome Methylation and Epigenomics) | Haematology | Biochemistry and Cell Biology | Genetics Not Elsewhere Classified | Cell Development (Incl. Cell Division And Apoptosis) | Genetic Development (Incl. Sex Determination) | Animal Physiology—Systems | Regenerative Medicine (incl. Stem Cells and Tissue Engineering) |
ANZSRC Socio-Economic Objective (SEO)
Blood disorders | Nervous system and disorders | Urogenital system and disorders | Expanding Knowledge in the Biological Sciences | Skin and related disorders | Reproductive system and disorders | Biological sciences | Organs, diseases and abnormal conditions not elsewhere classified
Related Links
Publications
Human KLF17 is a new member of the Sp/KLF family of transcription factors
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.YGENO.2005.12.011
Abstract: The Sp/KLF transcription factors perform a variety of biological functions, but are related in that they bind GC-box and CACCC-box sequences in DNA via a highly conserved DNA-binding domain. A database homology search, using the zinc finger DNA-binding domain characteristic of the family, has identified human KLF17 as a new family member that is most closely related to KLFs 1-8 and 12. KLF17 appears to be the human orthologue of the previously reported mouse gene, zinc finger protein 393 (Zfp393), although it has erged significantly. The DNA-binding domain is the most conserved region, suggesting that both the murine and the human forms recognize the same binding sites in DNA and may retain similar functions. We show that human KLF17 can bind G/C-rich sites via its zinc fingers and is able to activate transcription from CACCC-box elements. This is the first report of the DNA-binding characteristics and transactivation activity of human KLF17, which, together with the homology it displays to other KLF proteins, put it in the Sp/KLF family.
Erythroid Kruppel like factor: from fishing expedition to gourmet meal
Publisher: Elsevier BV
Date: 10-1999
DOI: 10.1016/S1357-2725(99)00083-7
Abstract: Erythroid Kruppel like factor (EKLF) is the founding member of a family of transcription factors which are defined by the presence of three C-terminal C2H2-type zinc fingers. Since its discovery 6 years ago, the study of EKLF has been intense. In this review I will revisit the discovery of EKLF, and highlight recent advances in our understanding of how it interacts with other proteins to regulate erythroid gene transcription. The current knowledge of the biological role/s of EKLF in erythroid cell differentiation and globin gene switching are summarized.
Silencing of human fetal globin expression is impaired in the absence of the adult β-globin gene activator protein EKLF
Publisher: Proceedings of the National Academy of Sciences
Date: 29-10-1996
Abstract: Globin genes are subject to tissue-specific and developmental stage-specific regulation. A switch from human fetal (gamma)-to adult (beta)-globin expression occurs within erythroid precursor cells of the adult lineage. Previously we and others showed by targeted gene disruption that the zinc finger gene, erythroid Krüppel-like factor (EKLF), is required for expression of the beta-globin gene in mice, presumably through interaction with a high-affinity binding site in the proximal promoter. To examine the role of EKLF in the developmental regulation of the human gamma-globin gene we interbred EKLF heterozygotes (+/-) with mice harboring a human beta-globin yeast artificial chromosome transgene. We find that in the absence of EKLF, while human beta-globin expression is dramatically reduced, gamma-globin transcripts are elevated approximately 5-fold. Impaired silencing of gamma-globin expression identifies EKLF as the first transcription factor participating quantitatively in the gamma-globin to beta-globin switch. Our findings are compatible with a competitive model of switching in which EKLF mediates an adult stage-specific interaction between the beta-globin gene promoter and the locus control region that excludes the gamma-globin gene.
Fibroblast growth factor-1 (FGF-1) promotes adipogenesis by downregulation of carboxypeptidase A4 (CPA4)–a negative regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity
Publisher: Informa UK Limited
Date: 11-2016
DOI: 10.1080/08977194.2017.1285764
Abstract: Fibroblast growth factor-1 (FGF-1) promotes differentiation of human preadipocytes into mature adipocytes via modulation of a BMP and Activin Membrane-Bound Inhibitor (BAMBI)/Peroxisome proliferator-activated receptor (PPARγ)-dependent network. Here, we combined transcriptomic and functional investigations to identify novel downstream effectors aligned with complementary analyses of gene expression in human adipose tissue to explore relationships with insulin sensitivity. RNA-Seq and qRT-PCR analysis revealed significant down-regulation of carboxypeptidase A4 (CPA4) following FGF-1 treatment or induction of differentiation of human preadipocytes in a BAMBI/PPARγ-independent manner. siRNA-mediated knockdown of CPA4 resulted in enhanced differentiation of human preadipocytes. Furthermore, expression of CPA4 in subcutaneous adipose tissue correlated negatively with indices of local and systemic (liver and muscle) insulin sensitivity. These results identify CPA4 as a negative regulator of adipogenesis that is down-regulated by FGF-1 and a putative deleterious modulator of local and systemic insulin sensitivity. Further investigations are required to define the molecular mechanism(s) involved and potential therapeutic opportunities.
BOREAS: a global, phase III study of the MDM2 inhibitor navtemadlin (KRT-232) in relapsed/refractory myelofibrosis.
Publisher: Future Medicine Ltd
Date: 12-2022
Abstract: Patients with myelofibrosis (MF) who discontinue ruxolitinib due to progression/resistance have poor prognoses. JAK inhibitors control symptoms and reduce spleen volumes with limited impact on underlying disease pathophysiology. Murine double minute 2 (MDM2), a negative regulator of p53, is overexpressed in circulating malignant CD34
Identification of novel hypomorphic and null mutations in Klf1 derived from a genetic screen for modifiers of α-globin transgene variegation.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.YGENO.2014.09.013
Abstract: Position-effect variegation of transgene expression is sensitive to the chromatin state. We previously reported a forward genetic screen in mice carrying a variegated α-globin GFP transgene to find novel genes encoding epigenetic regulators. We named the phenovariant strains "Mommes" for modifiers of murine metastable epialleles. Here we report positional cloning of mutations in two Momme strains which result in suppression of variegation. Both strains harbour point mutations in the erythroid transcription factor, Klf1. One (D11) generates a stop codon in the zinc finger domain and a homozygous null phenotype. The other (D45) generates an amino acid transversion (H350R) within a conserved linker between zinc fingers two and three. Homozygous MommeD45 mice have chronic microcytic anaemia which models the phenotype in a recently described family. This is the first genetic evidence that the linkers between the zinc fingers of transcription factors have a function beyond that of a simple spacer.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541173.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541170.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541182
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Macrophage Activation and Differentiation Signals Regulate Schlafen-4 Gene Expression: Evidence for Schlafen-4 as a Modulator of Myelopoiesis
Publisher: Public Library of Science (PLoS)
Date: 07-01-2011
Investigation of the variable In(Lu) phenotype caused by KLF1 variants
Publisher: Wiley
Date: 17-09-2018
DOI: 10.1111/TRF.14926
Abstract: KLF1 is an essential transcriptional activator that drives erythropoiesis. KLF1 variants can result in the Inhibitor of Lutheran, or In(Lu), phenotype where red blood cells (RBCs) have reduced BCAM (LU) and CD44 (IN). Other RBC surface molecules also have changed expression however, there is controversy in the literature regarding which are truly impacted. We aimed to investigate KLF1 variants in the Australian population. In(Lu) s les were sourced through screening and through the RBC reference laboratory. Blood donor s les (8036) were screened to identify weakened/absent Lu Four of 8036 donors were identified to be In(Lu), and two previously identified In(Lu) s les were provided from the RBC reference laboratory. Five different KLF1 variants were identified two were novel: c.954G>C .Trp318Cys and c.421C>T .Arg141*. BCAM and CD44 were reduced in all s les, consistent with previous reports. As a group, In(Lu) RBCs had reduced CD35 (KN), ICAM4 (LW), and CD147 (OK), and demonstrated increased binding of lectins ECA and SNAI. One In(Lu) s le had elevated HbF and another elevated HbA2. Different KLF1 variants may potentially produce variable phenotypes. A framework for investigating KLF1 variants and their phenotypic impact has been provided. In the future, given available international databases, further testing algorithms (as advocated here) will allow for correlation of phenotype with genotype and therefore accurately document this variability between KLF1 variants.
Variable serologic and other phenotypes due to KLF1 mutations.
Publisher: Wiley
Date: 23-04-2018
DOI: 10.1111/TRF.14529
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541188
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Myeloid somatic mutation panel testing in myeloproliferative neoplasms
Publisher: Elsevier BV
Date: 04-2021
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541185
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Diagnosis in subdural myeloid sarcoma
Publisher: SAGE Publications
Date: 30-01-2017
Abstract: A 74-year-old man presented to hospital with a headache, thrombocytopaenia and an acute deterioration in cognition on a background of acute monocytic leukaemia in remission. This is a case report with computed tomography (CT), magnetic resonance (MR) and histopathology imaging. Preoperative CT and limited MR demonstrated a subdural lesion with marked midline shift. Craniotomy performed for evacuation of the presumed subdural haematoma revealed a solid tumour-like lesion. Histopathology identified the presence of a myeloid sarcoma (chloroma). Postoperative MRI with contrast revealed the solid nature of the mass. The use of contrast is critical in the assessment of intracranial lesions to distinguish myeloid sarcoma from subdural haematoma in the context of leukaemia and a neurologically deteriorating patient.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541167.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
IMMUNE HEMOLYSIS AFTER ANABO MISMATCHED RENAL-TRANSPLANT
Publisher: Wiley
Date: 08-1989
DOI: 10.1111/J.1445-5994.1989.TB00275.X
Abstract: We describe a case of immune hemolysis due to anti-B occurring in a blood group B patient 16 days after a cadaveric renal transplantation from a blood group O donor. Transfusional support was initially required and the direct antiglobulin test (DAT) remained positive for 80 days. Cyclosporin A (CSA), which was used for rejection prophylaxis in this case, has unique immunosuppressive capabilities which protects transplanted organs from rejection, but which might permit this type of 'graft versus host' reaction.
LATE RELAPSES IN HODGKINS-DISEASE - ARE THEY A DISTINCT ENTITY
Publisher: Informa UK Limited
Date: 1991
DOI: 10.3109/10428199109068087
Abstract: It is claimed that late relapses of Hodgkin's disease have a good prognosis when retreated. A number of unfavourable outcomes led us to review our experience of 72 consecutive cases of Hodgkin's disease diagnosed and treated in a combined clinical haematology and radiation oncology unit between 1968 and 1984. 62 of 72 patients (86%) achieved a complete remission and of these, 35 patients (56%) relapsed, 18 occurring more than three years after diagnosis. Thus, 4 patient groups were identified: 10 patients with refractory disease, 27 patients who went into complete remission and have not relapsed, 17 patients who relapsed within 3 years of diagnosis (early relapse) and 18 patients who relapsed more than 3 years from diagnosis (late relapse). Patients who relapsed were retreated with well accepted protocols of chemotherapy and/or radiotherapy with surprisingly poor results. There was no significant difference between the survival from relapse of patients who relapsed early compared to those who relapsed late. Late relapses are not uncommon in Hodgkin's disease and the prognosis may be less favourable than generally perceived. The risk of relapse was almost constant with time and brings into question the concept of early and late relapse.
A global role for zebrafish klf4 in embryonic erythropoiesis
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.MOD.2007.06.005
Abstract: There are two waves of erythropoiesis, known as primitive and definitive waves in mammals and lower vertebrates including zebrafish. The founding member of the Kruppel-like factor (KLF) family of CACCC-box binding proteins, EKLF/Klf1, is essential for definitive erythropoiesis in mammals but only plays a minor role in primitive erythropoiesis. Morpholino knockdown experiments have shown a role for zebrafish klf4 in primitive erythropoiesis and hatching gland formation. In order to generate a global understanding of how klf4 might influence gene expression and differentiation, we have performed expression profiling of klf4 morphants, and then performed validation of many putative target genes by qRT-PCR and whole mount in situ hybridization. We found a critical role for klf4 in embryonic globin, heme synthesis and hatching gland gene expression. In contrast, there was an increase in expression of definitive hematopoietic specific genes such as larval globin genes, runx1 and c-myb from 24 hpf, suggesting a selective role for klf4 in primitive rather than definitive erythropoiesis. In addition, we show klf4 preferentially binds CACCC box elements in the primitive zebrafish beta-like globin gene promoters. These results have global implications for primitive erythroid gene regulation by KLF-CACCC box interactions.
Distinct domains of erythroid Kruppel-like factor modulate chromatin remodeling and transactivation at the endogenous beta-globin gene promoter
Publisher: Informa UK Limited
Date: 2002
JAK1 somatic mutation in a myeloproliferative neoplasm
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 26-05-2017
The EMT modulator SNAI1 contributes to AML pathogenesis via its interaction with LSD1
Publisher: American Society of Hematology
Date: 20-08-2020
Abstract: Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML.
Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia.
Publisher: Proceedings of the National Academy of Sciences
Date: 11-1990
Abstract: In the murine myelomonocytic leukemia WEHI-3B, proviral insertions have induced expression of the Hox-2.4 homeobox gene and the gene for the myeloid growth factor interleukin 3 (IL-3). To assess their potential oncogenic role, normal bone marrow cells were infected with retroviruses bearing the genes for IL-3 or IL-3 plus Hox-2.4. Unlike the IL-3 virus, the IL-3/Hox-2.4 virus was highly leukemogenic. Infected cells expressing both genes exhibited retarded differentiation in vitro, generated myelomonocytic cell lines, and provoked a rapid, transplantable myeloid leukemia in vivo. The oncogenic action of Hox-2.4 appears to derive from its ability to impede the IL-3-driven terminal differentiation of myeloid cells. The results suggest that homeobox genes can regulate key differentiation processes such as self-renewal capacity and that their inappropriate expression can be oncogenic.
Activation of stably silenced genes by recruitment of a synthetic de-methylating module
Publisher: Springer Science and Business Media LLC
Date: 23-09-2022
DOI: 10.1038/S41467-022-33181-4
Abstract: Stably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation of dCas9-based activation systems. To counter this, we create an improved activation system by coupling the catalytic domain of DNA demethylating enzyme TET1 with transcriptional activators (TETact). We show that TETact demethylation-coupled activation is able to induce transcription of suppressed genes, both in idually and simultaneously in cells, and has utility across a number of cell types. Furthermore, we show that TETact can effectively reactivate embryonic haemoglobin genes in non-erythroid cells. We anticipate that TETact will expand the existing CRISPR toolbox and be valuable for functional studies, genetic screens and potential therapeutics.
Supplementary Figure from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541194
Abstract: Supplementary Figure from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
New era for myelofibrosis treatment with novel agents beyond Janus kinase‐inhibitor monotherapy: Focus on clinical development of BCL‐XL/BCL‐2 inhibition with navitoclax
Publisher: Wiley
Date: 16-08-2023
DOI: 10.1002/CNCR.34986
Abstract: Myelofibrosis is a heterogeneous myeloproliferative neoplasm characterized by chronic inflammation, progressive bone marrow failure, and hepatosplenic extramedullary hematopoiesis. Treatments like Janus kinase inhibitor monotherapy (e.g., ruxolitinib) provide significant spleen and symptom relief but demonstrate limited ability to lead to a durable disease modification. There is an urgent unmet medical need for treatments with a novel mechanism of action that can modify the underlying pathophysiology and affect the disease course of myelofibrosis. This review highlights the role of B‐cell lymphoma (BCL) protein BCL‐extra large (BCL‐X L ) in disease pathogenesis and the potential role that navitoclax, a BCL‐extra large/BCL‐2 inhibitor, may have in myelofibrosis treatment.
Direct targets of pSTAT5 signalling in erythropoiesis.
Publisher: Public Library of Science (PLoS)
Date: 21-07-2017
Author Correction: EPO does not promote interaction between the erythropoietin and beta-common receptors.
Publisher: Springer Science and Business Media LLC
Date: 21-05-2019
DOI: 10.1038/S41598-019-43988-9
Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
C/EBPδ and C/EBPγ bind the CCAAT-box in the human β-globin promoter and modulate the activity of the CACC-box binding protein, EKLF
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.BBAEXP.2005.03.004
Abstract: Developmental- and tissue-specific expression of globin genes is mediated by a few key elements within the proximal promoter of each gene. DNA-binding assays previously identified NF-Y, GATA-1, C/EBPbeta and C/EBPgamma as candidate regulators of beta-globin transcription via the CCAAT-box, a promoter element situated between CACC- and TATA-boxes. We have identified C/EBPdelta as an additional beta-globin CCAAT-box binding protein. In reporter assays, we show that C/EBPdelta can co-operate with EKLF, a CACC-box binding protein, to activate the beta-globin promoter, whereas C/EBPgamma inhibits the transcriptional activity of EKLF in this assay.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541191
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541164.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
The transcriptional factor, IKAROS, plays a key role in γ–β globin gene switching
Publisher: Elsevier BV
Date: 03-2007
EPO does not promote interaction between the erythropoietin and beta-common receptors.
Publisher: Springer Science and Business Media LLC
Date: 20-08-2018
DOI: 10.1038/S41598-018-29865-X
Abstract: A direct interaction between the erythropoietin (EPOR) and the beta-common (βc) receptors to form an Innate Repair Receptor (IRR) is controversial. On one hand, studies have shown a functional link between EPOR and βc receptor in tissue protection while others have shown no involvement of the βc receptor in tissue repair. To date there is no biophysical evidence to confirm a direct association of the two receptors either in vitro or in vivo . We investigated the existence of an interaction between the extracellular regions of EPOR and the βc receptor in silico and in vitro (either in the presence or absence of EPO or EPO-derived peptide ARA290). Although a possible interaction between EPOR and βc was suggested by our computational and genomic studies, our in vitro biophysical analysis demonstrates that the extracellular regions of the two receptors do not specifically associate. We also explored the involvement of the βc receptor gene ( Csf2rb ) under anaemic stress conditions and found no requirement for the βc receptor in mice. In light of these studies, we conclude that the extracellular regions of the EPOR and the βc receptor do not directly interact and that the IRR is not involved in anaemic stress.
KLF1 directly coordinates almost all aspects of terminal erythroid differentiation
Publisher: Wiley
Date: 12-2010
DOI: 10.1002/IUB.404
Abstract: The molecular events and transcriptional mechanisms that underlie erythropoiesis are of great interest to biologists and hematologists since disorders of erythrocytes are common and remain relatively poorly understood. Kruppel-like factor 1 (KLF1) is a critical transcription factor for erythropoiesis in mice and man. Recently the use of chromatin immunoprecipitation (ChIP) coupled to next-generation DNA sequencing (ChIP-seq) has led to an updated understanding of how KLF1 functions in vivo. The full extent of KLF1 target genes have provided new insights into erythropoiesis, and have established that KLF1 controls almost all aspects of erythroid cell development and maturation.
Human ERMAP: An Erythroid Adhesion/Receptor Transmembrane Protein
Publisher: Elsevier BV
Date: 09-2001
Indian hedgehog supports definitive erythropoiesis
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.BCMD.2009.04.004
Abstract: Indian hedgehog (Ihh) has been reported to stimulate haematopoiesis ex vivo. In this study we studied the consequences of loss of function of Ihh for murine haematopoietic development. Ihh has no essential role in primitive erythropoiesis, but it is required in a non cell autonomous fashion for definitive erythropoieisis. Many components of the hedgehog signaling pathway are present in the fetal liver, with Ihh and Gli1 being most highly expressed in the stroma and Ptc1 being most highly expressed in haematopoietic stem and progenitor cells. Ihh knockout HSC and progenitor cell populations are produced in normal numbers in vivo and respond normally to haematopoietic cytokines in vitro, but terminal erythroid differentiation is defective leading to fatal anemia in mid gestation in many Ihh knockout embryos. These loss-of-function studies are consistent with previous gain-of-function studies which show Ihh can induce blood from ectoderm or expand HSCs in stroma-dependent culture.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541191.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia
Publisher: Springer Science and Business Media LLC
Date: 15-06-2020
DOI: 10.1038/S41467-020-16840-2
Abstract: The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.
Novel roles for KLF1 in erythropoiesis revealed by mRNA-seq
Publisher: Cold Spring Harbor Laboratory
Date: 26-07-2012
Abstract: KLF1 (formerly known as EKLF) regulates the development of erythroid cells from bi-potent progenitor cells via the transcriptional activation of a erse set of genes. Mice lacking Klf1 die in utero prior to E15 from severe anemia due to the inadequate expression of genes controlling hemoglobin production, cell membrane and cytoskeletal integrity, and the cell cycle. We have recently described the full repertoire of KLF1 binding sites in vivo by performing KLF1 ChIP-seq in primary erythroid tissue (E14.5 fetal liver). Here we describe the KLF1-dependent erythroid transcriptome by comparing mRNA-seq from Klf1 +/+ and Klf1 −/− erythroid tissue. This has revealed novel target genes not previously obtainable by traditional microarray technology, and provided novel insights into the function of KLF1 as a transcriptional activator. We define a cis -regulatory module bound by KLF1, GATA1, TAL1, and EP300 that coordinates a core set of erythroid genes. We also describe a novel set of erythroid-specific promoters that drive high-level expression of otherwise ubiquitously expressed genes in erythroid cells. Our study has identified two novel lncRNAs that are dynamically expressed during erythroid differentiation, and discovered a role for KLF1 in directing apoptotic gene expression to drive the terminal stages of erythroid maturation.
Zebrafish klf4 plays a global role in primitive erythropoiesis
Publisher: Elsevier BV
Date: 03-2007
Supplementary Figure from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541194.V1
Abstract: Supplementary Figure from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Krüppel-like factor
Publisher: American Society of Hematology
Date: 07-08-2014
DOI: 10.1182/BLOOD-2013-11-539718
Abstract: Heme-bound iron activates placenta growth factor expression in erythroid cells via EKLF, a crucial erythroid-specific transcription factor. Markers of iron burden predict mortality in adults with sickle cell disease.
Impact of the c-MybE308G mutation on mouse myelopoiesis and dendritic cell development
Publisher: Public Library of Science (PLoS)
Date: 26-04-2017
Complex architecture and regulated expression of the Sox2ot locus during vertebrate development.
Publisher: Cold Spring Harbor Laboratory
Date: 18-09-2009
DOI: 10.1261/RNA.1705309
Abstract: The Sox2 gene is a key regulator of pluripotency embedded within an intron of a long noncoding RNA (ncRNA), termed Sox2 overlapping transcript ( Sox2ot ), which is transcribed in the same orientation. However, this ncRNA remains uncharacterized. Here we show that Sox2ot has multiple transcription start sites associated with genomic features that indicate regulated expression, including highly conserved elements (HCEs) and chromatin marks characteristic of gene promoters. To identify biological processes in which Sox2ot may be involved, we analyzed its expression in several developmental systems, compared to expression of Sox2 . We show that Sox2ot is a stable transcript expressed in mouse embryonic stem cells, which, like Sox2 , is down-regulated upon induction of embryoid body (EB) differentiation. However, in contrast to Sox2 , Sox2ot is up-regulated during EB mesoderm-lineage differentiation. In adult mouse, Sox2ot isoforms were detected in tissues where Sox2 is expressed, as well as in different tissues, supporting independent regulation of expression of the ncRNA. Sox2dot , an isoform of Sox2ot transcribed from a distal HCE located kb upstream of Sox2 , was detected exclusively in the mouse brain, with enrichment in regions of adult neurogenesis. In addition, Sox2ot isoforms are transcribed from HCEs upstream of Sox2 in other vertebrates, including in several regions of the human brain. We also show that Sox2ot is dynamically regulated during chicken and zebrafish embryogenesis, consistently associated with central nervous system structures. These observations provide insight into the structure and regulation of the Sox2ot gene, and suggest conserved roles for Sox2ot orthologs during vertebrate development.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541188.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Enrichment of blood from embryonic stem cells in vitro
Publisher: CSIRO Publishing
Date: 1998
DOI: 10.1071/RD98104
Abstract: Murine embryonic stem (ES) cells are pluripotent. When injected into blastocysts they can give rise to every cell type of a derived chimeric mouse including germ cells. Embryonic stem cells also possess remarkable in vitro differentiation potential. When removed from stromal support and leukaemia inhibitory factor (LIF), ES cells differentiate into structures known as embryoid bodies (EBs), in which all three germ layers develop and interact. As ES cells from humans become available there is increasing interest in the potential for EBs to provide an unlimited supply of stem cells for somatic transplantation therapies. Realisation of this potential will require greater understanding of the molecular determinants of cell fate within EBs. Also, culture techniques for selective expansion of cell lineages of interest will reduce the risks associated with transplantation of EB-derived cells. In this paper the kinetics of expression of mRNA and protein for early mesoderm markers within EBs is reported. In addition, a three-step culture system incorporating co-cultivation on the bone marrow derived stromal cell line, MC3T3-G2/PA6 (PA6), is explored as a way to select for haematopoietic progenitor cells (HPCs) and against undifferentiated ES cells. A system like this could enhance purification of haematopoietic stem cells (HSCs) from ES cells for bone marrow transplantation.
The Evx1/Evx1as gene locus regulates anterior-posterior patterning during gastrulation.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2016
DOI: 10.1038/SREP26657
Abstract: Thousands of sense-antisense mRNA-lncRNA gene pairs occur in the mammalian genome. While there is usually little doubt about the function of the coding transcript, the function of the lncRNA partner is mostly untested. Here we examine the function of the homeotic Evx1 - Evx1as gene locus. Expression is tightly co-regulated in posterior mesoderm of mouse embryos and in embryoid bodies. Expression of both genes is enhanced by BMP4 and WNT3A, and reduced by Activin. We generated a suite of deletions in the locus by CRISPR-Cas9 editing. We show EVX1 is a critical downstream effector of BMP4 and WNT3A with respect to patterning of posterior mesoderm. The lncRNA, Evx1as arises from alternative promoters and is difficult to fully abrogate by gene editing or siRNA approaches. Nevertheless, we were able to generate a large 2.6 kb deletion encompassing the shared promoter with Evx1 and multiple additional exons of Evx1as. This led to an identical dorsal-ventral patterning defect to that generated by micro-deletion in the DNA-binding domain of EVX1. Thus, Evx1as has no function independent of EVX1, and is therefore unlikely to act in trans . We predict many antisense lncRNAs have no specific trans function, possibly only regulating the linked coding genes in cis .
Kruppel-like factors compete for promoters and enhancers to fine-tune transcription
Publisher: Oxford University Press (OUP)
Date: 24-05-2017
DOI: 10.1093/NAR/GKX441
Corrupted DNA-binding specificity and ectopic transcription underpin dominant neomorphic mutations in KLF/SP transcription factors.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2019
Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation
Publisher: Cold Spring Harbor Laboratory
Date: 18-06-2008
Abstract: The transcriptional networks that regulate embryonic stem (ES) cell pluripotency and lineage specification are the subject of considerable attention. To date such studies have focused almost exclusively on protein-coding transcripts. However, recent transcriptome analyses show that the mammalian genome contains thousands of long noncoding RNAs (ncRNAs), many of which appear to be expressed in a developmentally regulated manner. The functions of these remain untested. To identify ncRNAs involved in ES cell biology, we used a custom-designed microarray to examine the expression profiles of mouse ES cells differentiating as embryoid bodies (EBs) over a 16-d time course. We identified 945 ncRNAs expressed during EB differentiation, of which 174 were differentially expressed, many correlating with pluripotency or specific differentiation events. Candidate ncRNAs were identified for further characterization by an integrated examination of expression profiles, genomic context, chromatin state, and promoter analysis. Many ncRNAs showed coordinated expression with genomically associated developmental genes, such as Dlx1 , Dlx4 , Gata6 , and Ecsit . We examined two novel developmentally regulated ncRNAs, Evx1as and Hoxb5/6as , which are derived from homeotic loci and share similar expression patterns and localization in mouse embryos with their associated protein-coding genes. Using chromatin immunoprecipitation, we provide evidence that both ncRNAs are associated with trimethylated H3K4 histones and histone methyltransferase MLL1, suggesting a role in epigenetic regulation of homeotic loci during ES cell differentiation. Taken together, our data indicate that long ncRNAs are likely to be important in processes directing pluripotency and alternative differentiation programs, in some cases through engagement of the epigenetic machinery.
Data from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549562
Abstract: Abstract Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies. Significance: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. i This article is highlighted in the In This Issue feature, p. 1397 /i /
High resolution temporal transcriptomics of mouse embryoid body development reveals complex expression dynamics of coding and noncoding loci
Publisher: Springer Science and Business Media LLC
Date: 27-07-2017
DOI: 10.1038/S41598-017-06110-5
Abstract: Cellular responses to stimuli are rapid and continuous and yet the vast majority of investigations of transcriptional responses during developmental transitions typically use long interval time courses limiting the available interpretive power. Moreover, such experiments typically focus on protein-coding transcripts, ignoring the important impact of long noncoding RNAs. We therefore evaluated coding and noncoding expression dynamics at unprecedented temporal resolution (6-hourly) in differentiating mouse embryonic stem cells and report new insight into molecular processes and genome organization. We present a highly resolved differentiation cascade that exhibits coding and noncoding transcriptional alterations, transcription factor network interactions and alternative splicing events, little of which can be resolved by long-interval developmental time-courses. We describe novel short lived and cycling patterns of gene expression and dissect temporally ordered gene expression changes in response to transcription factors. We elucidate patterns in gene co-expression across the genome, describe asynchronous transcription at bidirectional promoters and functionally annotate known and novel regulatory lncRNAs. These findings highlight the complex and dynamic molecular events underlying mammalian differentiation that can only be observed though a temporally resolved time course.
Rapid Molecular Profiling of Myeloproliferative Neoplasms Using Targeted Exon Resequencing of 86 Genes Involved in JAK-STAT Signaling and Epigenetic Regulation
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.JMOLDX.2016.05.006
Abstract: Myeloproliferative neoplasms (MPNs) are a heterogeneous group of blood disorders characterized by excess production of mature blood cells and an increased risk of late transformation to acute myeloid leukemia or primary myelofibrosis. Approximately 15% of MPN cases do not carry mutations in JAK2, CALR, or MPL and are thus often referred to as triple-negative cases. These are caused by a erse set of rare mutations in cytokine receptors, JAK-STAT signaling pathway components, or epigenetic modifiers. In addition, some cases diagnosed as MPN are reactive rather than clonal disorders, so a negative result from a genetic screen can be informative. To obtain a comprehensive rapid molecular diagnosis for most MPNs, we developed an assay to detect genetic mutations (single nucleotide variants and/or small insertions/deletions) in 86 genes using targeted exon resequencing (AmpliSeq) and a bench-top semiconductor machine (Ion Torrent Personal Genome Machine). Our assay reliably detects well characterized mutations in JAK2, CALR, and MPL, but also rarer mutations in ASXL1, TET2, SH2B3, and other genes. Some of these mutations are novel. We find multiple mutations in advanced cases, suggesting co-operation between Janus kinase-STAT pathway mutations and epigenetic mutations in disease progression. This assay can be used to follow molecular progression, clonal heterogeneity, and drug resistance in MPNs.
Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 21-03-2022
DOI: 10.1158/2159-8290.CD-20-1145
Abstract: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. This article is highlighted in the In This Issue feature, p. 1397
Prediction of novel long non-coding RNAs based on RNA-Seq data of mouse Klf1 knockout study
Publisher: Springer Science and Business Media LLC
Date: 12-2012
Abstract: Study on long non-coding RNAs (lncRNAs) has been promoted by high-throughput RNA sequencing (RNA-Seq). However, it is still not trivial to identify lncRNAs from the RNA-Seq data and it remains a challenge to uncover their functions. We present a computational pipeline for detecting novel lncRNAs from the RNA-Seq data. First, the genome-guided transcriptome reconstruction is used to generate initially assembled transcripts. The possible partial transcripts and artefacts are filtered according to the quantified expression level. After that, novel lncRNAs are detected by further filtering known transcripts and those with high protein coding potential, using a newly developed program called lncRScan. We applied our pipeline to a mouse Klf1 knockout dataset, and discussed the plausible functions of the novel lncRNAs we detected by differential expression analysis. We identified 308 novel lncRNA candidates, which have shorter transcript length, fewer exons, shorter putative open reading frame, compared with known protein-coding transcripts. Of the lncRNAs, 52 large intergenic ncRNAs (lincRNAs) show lower expression level than the protein-coding ones and 13 lncRNAs represent significant differential expression between the wild-type and Klf1 knockout conditions. Our method can predict a set of novel lncRNAs from the RNA-Seq data. Some of the lncRNAs are showed differentially expressed between the wild-type and Klf1 knockout strains, suggested that those novel lncRNAs can be given high priority in further functional studies.
HIF prolyl hydroxylase inhibitor FG-4497 enhances mouse hematopoietic stem cell mobilization via VEGFR2/KDR
Publisher: American Society of Hematology
Date: 07-02-2019
The F-BAR protein NOSTRIN participates in FGF signal transduction and vascular development
Publisher: Wiley
Date: 29-06-2012
Congenital fibrinogen disorders: Strengthening genotype–phenotype correlations through novel genetic diagnostic tools
Publisher: Wiley
Date: 15-08-2023
DOI: 10.1111/BJH.19039
Abstract: Congenital fibrinogen disorders or CFDs are heterogenous, both in clinical manifestation and array of culprit molecular lesions. Correlations between phenotype and genotype remain poorly defined. This review examines the genetic landscape discovered to date for this rare condition. The question of a possible oligogenic model of inheritance influencing phenotypic heterogeneity is raised, with discussion of the benefits and challenges of sequencing technology used to enhance discovery in this space. Considerable work lies ahead in order to achieve diagnostic and prognostic precision and subsequently provide targeted management to this complex cohort of patients.
Genomic organisation and regulation of murine alpha haemoglobin stabilising protein by erythroid Kruppel-like factor
Publisher: Wiley
Date: 27-10-2007
DOI: 10.1111/J.1365-2141.2006.06381.X
Abstract: Alpha haemoglobin stabilising protein (AHSP) binds free alpha-globin chains and plays an important role in the protection of red cells, particularly during beta-thalassaemia. Murine ASHP was discovered as a GATA-1 target gene and human AHSP is directly regulated by GATA-1. More recently, AHSP was rediscovered as a highly erythroid Kruppel-like factor (EKLF) -dependent transcript. We have determined the organisation of the murine AHSP gene and compared it to orthologs. There are two CACC box elements in the proximal promoter. The proximal element is absolutely conserved, but does not bind EKLF as it is not a canonical binding site. In rodents, the distal element contains a 3 bp insertion that disrupts the typical EKLF binding consensus region. Nevertheless, EKLF binds this atypical site by gel mobility shift assay, specifically occupies the AHSP promoter in vivo in a chromatin immunoprecipitation assay, and transactivates AHSP through this CACC site in promoter-reporter assays. Our results suggest EKLF can occupy CACC elements in vivo that are not predictable from the consensus binding site inferred from structural studies. We also propose that absence of AHSP in EKLF-null red cells exacerbates the toxicity of free alpha-globin chains, which exist because of the defect in beta-globin gene activation.
Developing empirical formulations to predict residual strength and damages in tension-leg platform hulls after a collision
Publisher: Elsevier BV
Date: 10-2023
Fragmentation of macrophages during isolation confounds analysis of single cell preparations from mouse hematopoietic tissues
Publisher: Cold Spring Harbor Laboratory
Date: 28-04-2021
DOI: 10.1101/2021.04.28.441876
Abstract: Mouse hematopoietic tissues contain abundant and heterogeneous populations of tissue-resident macrophages attributed trophic functions in control of immunity, hematopoiesis and bone homeostasis. A systematic strategy to characterise macrophage subsets in mouse bone marrow (BM), spleen and lymph node, unexpectedly revealed macrophage surface marker staining typically emanated from membrane-bound subcellular remnants associated with unrelated cell types. Remnant-restricted macrophage-specific membrane markers, cytoplasmic fluorescent reporters and mRNA were all detected in non-macrophage cell populations including isolated stem and progenitor cells. The profile of macrophage remnant association reflects adhesive interactions between macrophages and other cell types in vivo. Applying this knowledge, reduced macrophage remnant attachment to BM granulocytes in Siglec1 deficient mice was associated with compromised emergency granulocytosis, revealing a function for Siglec1 -dependent granulocyte-macrophage interactions. Analysis of published RNA-seq data for purified macrophage and non-macrophage populations indicates that macrophage fragmentation is a general phenomenon that confounds bulk and single cell analysis of disaggregated tissues.
Macrophages and regulation of erythropoiesis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 23-01-2015
Data from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549562.V1
Abstract: Abstract Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies. Significance: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. i This article is highlighted in the In This Issue feature, p. 1397 /i /
Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
DOI: 10.1038/S41467-020-15817-5
Abstract: The endothelial cell adhesion molecule E-selectin is a key component of the bone marrow hematopoietic stem cell (HSC) vascular niche regulating balance between HSC self-renewal and commitment. We now report in contrast, E-selectin directly triggers signaling pathways that promote malignant cell survival and regeneration. Using acute myeloid leukemia (AML) mouse models, we show AML blasts release inflammatory mediators that upregulate endothelial niche E-selectin expression. Alterations in cell-surface glycosylation associated with oncogenesis enhances AML blast binding to E-selectin and enable promotion of pro-survival signaling through AKT/NF-κB pathways. In vivo AML blasts with highest E-selectin binding potential are 12-fold more likely to survive chemotherapy and main contributors to disease relapse. Absence (in Sele −/− hosts) or therapeutic blockade of E-selectin using small molecule mimetic GMI-1271/Uproleselan effectively inhibits this niche-mediated pro-survival signaling, d ens AML blast regeneration, and strongly synergizes with chemotherapy, doubling the duration of mouse survival over chemotherapy alone, whilst protecting endogenous HSC.
Ermap, a gene coding for a novel erythroid specific adhesion/receptor membrane protein
Publisher: Elsevier BV
Date: 2000
DOI: 10.1016/S0378-1119(99)00516-8
Abstract: Ermap (erythroid membrane-associated protein), a gene coding for a novel transmembrane protein produced exclusively in erythroid cells, is described. It is mapped to murine Chromosome 4, 57 cM distal to the centromere. The initial cDNA clone was isolated from a day 9 murine embryonic erythroid cell cDNA library. The predicted peptide sequence suggests that ERMAP is a transmembrane protein with two extracellular immunoglobulin folds, as well as a highly conserved B30.2 domain and several phosphorylation consensus sequences in the cytoplasmic region. ERMAP shares a high homology throughout the entire peptide with butyrophilin, a glycoprotein essential for milk lipid droplet formation and release. A GFP-ERMAP fusion protein was localized to the plasma membrane and cytoplasmic vesicles in transiently transfected 293T cells. Northern blot analysis and in-situ hybridization demonstrated that Ermap expression was restricted to fetal and adult erythroid tissues. ERMAP is likely a novel adhesion/receptor molecule specific for erythroid cells.
Interaction of c-Myb with p300 is required for the induction of acute myeloid leukemia (AML) by human AML oncogenes
Publisher: American Society of Hematology
Date: 24-04-2014
DOI: 10.1182/BLOOD-2012-02-413187
Abstract: A mutation preventing interaction between c-Myb and p300 prevents transformation and leukemia induction by MLL-AF9 and AML1-ETO9a oncogenes. Identifying agents that block the c-Myb-p300 interaction may be a valuable approach to developing a therapy for acute myeloid leukemia.
Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment
Publisher: American Society of Hematology
Date: 16-08-2018
DOI: 10.1182/BLOOD-2018-01-829663
Abstract: Recipient macrophages persist in hematopoietic tissues and self-repopulate via in situ proliferation after syngeneic transplantation. Targeted depletion of recipient CD169+ macrophages after transplant impaired long-term bone marrow engraftment of hematopoietic stem cells.
Stem cell transcriptome profiling via massive-scale mRNA sequencing
Publisher: Springer Science and Business Media LLC
Date: 30-05-2008
DOI: 10.1038/NMETH.1223
Abstract: We developed a massive-scale RNA sequencing protocol, short quantitative random RNA libraries or SQRL, to survey the complexity, dynamics and sequence content of transcriptomes in a near-complete fashion. This method generates directional, random-primed, linear cDNA libraries that are optimized for next-generation short-tag sequencing. We surveyed the poly(A)(+) transcriptomes of undifferentiated mouse embryonic stem cells (ESCs) and embryoid bodies (EBs) at an unprecedented depth (10 Gb), using the Applied Biosystems SOLiD technology. These libraries capture the genomic landscape of expression, state-specific expression, single-nucleotide polymorphisms (SNPs), the transcriptional activity of repeat elements, and both known and new alternative splicing events. We investigated the impact of transcriptional complexity on current models of key signaling pathways controlling ESC pluripotency and differentiation, highlighting how SQRL can be used to characterize transcriptome content and dynamics in a quantitative and reproducible manner, and suggesting that our understanding of transcriptional complexity is far from complete.
Dynamic transcription programs during ES cell differentiation towards mesoderm in serum versus serum-freeBMP4 culture
Publisher: Springer Science and Business Media LLC
Date: 10-10-2007
Abstract: Expression profiling of embryonic stem (ES) cell differentiation in the presence of serum has been performed previously. It remains unclear if transcriptional activation is dependent on complex growth factor mixtures in serum or whether this process is intrinsic to ES cells once the stem cell program has been inactivated. The aims of this study were to determine the transcriptional programs associated with the stem cell state and to characterize mesoderm differentiation between serum and serum-free culture. ES cells were differentiated as embryoid bodies in 10% FBS or serum-free media containing BMP4 (2 ng/ml), and expression profiled using 47 K Illumina(R) Sentrix arrays. Statistical methods were employed to define gene sets characteristic of stem cell, epiblast and primitive streak programs. Although the initial differentiation profile was similar between the two culture conditions, cardiac gene expression was inhibited in serum whereas blood gene expression was enhanced. Also, expression of many members of the Kruppel-like factor (KLF) family of transcription factors changed dramatically during the first few days of differentiation. KLF2 and KLF4 co-localized with OCT4 in a sub-nuclear compartment of ES cells, dynamic changes in KLF-DNA binding activities occurred upon differentiation, and strong bio-informatic evidence for direct regulation of many stem cell genes by KLFs was found. Down regulation of stem cell genes and activation of epiblast rimitive streak genes is similar in serum and defined media, but subsequent mesoderm differentiation is strongly influenced by the composition of the media. In addition, KLF family members are likely to be important regulators of many stem cell genes.
Evolution of gene function and regulatory control after whole-genome duplication: Comparative analyses in vertebrates
Publisher: Cold Spring Harbor Laboratory
Date: 13-05-2009
Abstract: The significance of whole-genome duplications (WGD) for vertebrate evolution remains controversial, in part because the mechanisms by which WGD contributed to functional evolution or speciation are still incompletely characterized. Fish genomes provide an ideal context in which to examine the consequences of WGD, because the teleost lineage experienced an additional WGD soon after ergence from tetrapods and because five teleost genomes are available for comparative analysis. Here we present an integrated approach to characterize these post-duplication genomes based on genome-scale synteny, phylogenetic, temporal, and spatial gene expression and on protein sequence data. A minimum of 3%–4% of protein-coding loci have been retained in two copies in each of the five fish genomes, and many of these duplicates are key developmental genes that function as transcription factors or signaling molecules. Almost all duplicate gene pairs we examined have erged in spatial and/or temporal expression during embryogenesis. A quarter of duplicate pairs have erged in function via the acquisition of novel protein domains or via changes in the subcellular localization of their encoded proteins. We compared the spatial expression and protein domain architecture of zebrafish WGD-duplicates to those of their single mouse ortholog and found many ex les supporting a model of neofunctionalization. WGD-duplicates have acquired novel protein domains more often than have single-copy genes. Post-WGD changes at the gene regulatory level were more common than changes at the protein level. We conclude that the most significant consequence of WGD for vertebrate evolution has been to enable more-specialized regulatory control of development via the acquisition of novel spatiotemporal expression domains. We find limited evidence that reciprocal gene loss led to reproductive isolation and speciation in this lineage.
SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis
Publisher: Proceedings of the National Academy of Sciences
Date: 09-06-1998
Abstract: SEK1 (MKK4/JNKK) is a mitogen-activated protein kinase activator that has been shown to participate in vitro in two stress-activated cascades terminating with the SAPK and p38 kinases. To define the role of SEK1 in vivo , we studied stress-induced signaling in SEK1 −/− embryonic stem and fibroblast cells and evaluated the phenotype of SEK1 −/− mouse embryos during development. Studies of SEK1 −/− embryonic stem cells demonstrated defects in stimulated SAPK phosphorylation but not in the phosphorylation of p38 kinase. In contrast, SEK1 −/− fibroblasts exhibited defects in both SAPK and p38 phosphorylation, demonstrating that crosstalk exists between the stress-activated cascades. Tumor necrosis factor α and interleukin 1 stimulation of both stress-activated cascades are severely affected in the SEK1 −/− fibroblast cells. SEK1 deficiency leads to embryonic lethality after embryonic day 12.5 and is associated with abnormal liver development. This phenotype is similar to c-jun null mouse embryos and suggests that SEK1 is required for phosphorylation and activation of c-jun during the organo-genesis of the liver.
KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome
Publisher: American Society of Hematology
Date: 09-04-2015
DOI: 10.1182/BLOOD-2014-08-590968
Abstract: Complete loss of KLF1 function is compatible with life but results in severe nonspherocytic hemolytic anemia and kernicterus. Human KLF1 regulates most aspects of red cell biology.
Mutant KLF1 in Adult Anemic Nan Mice Leads to Profound Transcriptome Changes and Disordered Erythropoiesis
Publisher: Springer Science and Business Media LLC
Date: 24-08-2018
DOI: 10.1038/S41598-018-30839-2
Abstract: Anemic Nan mice carry a mutation (E339D) in the second zinc finger of erythroid transcription factor KLF1. Nan-KLF1 fails to bind a subset of normal KLF1 targets and ectopically binds a large set of genes not normally engaged by KLF1, resulting in a corrupted fetal liver transcriptome. Here, we performed RNAseq using flow cytometric-sorted spleen erythroid precursors from adult Nan and WT littermates rendered anemic by phlebotomy to identify global transcriptome changes specific to the Nan Klf1 mutation as opposed to anemia generally. Mutant Nan-KLF1 leads to extensive and progressive transcriptome corruption in adult spleen erythroid precursors such that stress erythropoiesis is severely compromised. Terminal erythroid differentiation is defective in the bone marrow as well. Principle component analysis reveals two major patterns of differential gene expression predicting that defects in basic cellular processes including translation, cell cycle, and DNA repair could contribute to disordered erythropoiesis and anemia in Nan . Significant erythroid precursor stage specific changes were identified in some of these processes in Nan . Remarkably, however, despite expression changes in large numbers of associated genes, most basic cellular processes were intact in Nan indicating that developing red cells display significant physiological resiliency and establish new homeostatic set points in vivo .
The Role of LNK (SH2B3) in the Regulation of JAK-STAT Signalling in Haematopoiesis
Publisher: MDPI AG
Date: 24-12-2021
DOI: 10.3390/PH15010024
Abstract: LNK is a member of the SH2B family of adaptor proteins and is a non-redundant regulator of cytokine signalling. Cytokines are secreted intercellular messengers that bind to specific receptors on the surface of target cells to activate the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling pathway. Activation of the JAK-STAT pathway leads to proliferative and often inflammatory effects, and so the litude and duration of signalling are tightly controlled. LNK binds phosphotyrosine residues to signalling proteins downstream of cytokines and constrains JAK-STAT signalling. Mutations in LNK have been identified in a range of haematological and inflammatory diseases due to increased signalling following the loss of LNK function. Here, we review the regulation of JAK-STAT signalling via the adaptor protein LNK and discuss the role of LNK in haematological diseases.
neptune, a Kruppel-like transcription factor that participates in primitive erythropoiesis in Xenopus
Publisher: Elsevier BV
Date: 09-2001
DOI: 10.1016/S0960-9822(01)00427-4
Abstract: The specification of the erythroid lineage from hematopoietic stem cells requires the expression and activity of lineage-specific transcription factors. One transcription factor family that has several members involved in hematopoiesis is the Krüppel-like factor (KLF) family [1]. For ex le, erythroid KLF (EKLF) regulates beta-globin expression during erythroid differentiation [2-6]. KLFs share a highly conserved zinc finger-based DNA binding domain (DBD) that mediates binding to CACCC-box and GC-rich sites, both of which are frequently found in the promoters of hematopoietic genes. Here, we identified a novel Xenopus KLF gene, neptune, which is highly expressed in the ventral blood island (VBI), cranial ganglia, and hatching and cement glands. neptune expression is induced in response to components of the BMP-4 signaling pathway in injected animal cap explants. Similar to its family member, EKLF, Neptune can bind CACCC-box and GC-rich DNA elements. We show that Neptune cooperates with the hematopoietic transcription factor XGATA-1 to enhance globin induction in animal cap explants. A fusion protein comprised of Neptune's DBD and the Drosophila engrailed repressor domain suppresses the induction of globin in ventral marginal zones and in animal caps. These studies demonstrate that Neptune is a positive regulator of primitive erythropoiesis in Xenopus.
Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial
Publisher: Elsevier BV
Date: 05-2017
A Novel RUNX1 Genetic Variant Identified in a Young Male with Severe Osteoporosis
Publisher: Wiley
Date: 29-07-2023
DOI: 10.1002/JBM4.10791
Abstract: This case describes a young man with an unusual cause of severe osteoporosis and markedly deranged bone microarchitecture resulting in multiple fractures. A potentially pathogenic germline variant in the runt‐related transcription factor 1 (RUNX1) gene was discovered by a focused 51‐gene myeloid malignancy panel during investigation for his unexplained normochromic normocytic anemia. Further bone‐specific genetic testing and a pedigree analysis were declined by the patient. Recent experimental evidence demonstrates that RUNX1 plays a key role in the regulation of osteogenesis and bone homeostasis during skeletal development, mediated by the bone morphogenic protein and Wnt signaling pathways. Therefore, rarer causes of osteoporosis, including those affecting bone formation, should be considered in young patients with multiple unexpected minimal trauma fractures. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Widespread Failure of Hematolymphoid Differentiation Caused by a Recessive Niche-Filling Allele of the Ikaros Transcription Factor
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S1074-7613(03)00168-7
Abstract: A central issue in understanding the hematolymphoid system is the generation of appropriate mutant alleles in mice to reveal the function of regulatory genes. Here we describe a mouse strain, Plastic, with a point mutation in a zinc finger of Ikaros that disrupts DNA binding but preserves efficient assembly of the full-length protein into higher order complexes. Ikaros(Plastic) homozygosity is embryonically lethal with severe defects in terminal erythrocyte and granulocyte differentiation, excessive macrophage formation, and blocked lymphopoiesis, while heterozygotes display a partial block in lymphocyte differentiation. The contrast with more circumscribed effects of Ikaros alleles that ablate the full-length protein highlights the importance in mammals of generating recessive niche-filling alleles that inactivate function without creating a void in multimolecular assemblies.
A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells.
Publisher: Cold Spring Harbor Laboratory
Date: 27-05-2010
Abstract: KLF1 regulates a erse suite of genes to direct erythroid cell differentiation from bipotent progenitors. To determine the local cis -regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.5 fetal liver erythroid cells which are occupied by endogenous KLF1. Many of these recovered sites reside in erythroid gene promoters such as Hbb-b1 , but the majority are distant to any known gene. Our data suggests KLF1 directly regulates most aspects of terminal erythroid differentiation including production of alpha- and beta-globin protein chains, heme biosynthesis, coordination of proliferation and anti-apoptotic pathways, and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptional activator. Additionally, we suggest new mechanisms for KLF1 cooperation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment.
Megakaryocyte-erythroid lineage promiscuity in EKLF null mouse blood
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 22-10-2009
Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development
Publisher: The Company of Biologists
Date: 02-2017
DOI: 10.1242/DEV.145656
Abstract: Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.
The regulation of gene repression by BKLF
Publisher: Elsevier BV
Date: 03-2007
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541185.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Low PIP2 molar fractions induce nanometer size clustering in giant unilamellar vesicles
Publisher: Elsevier BV
Date: 2014
MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic
Publisher: Future Medicine Ltd
Date: 04-2021
Abstract: Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541179.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541167
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability
Publisher: Oxford University Press (OUP)
Date: 24-11-2017
DOI: 10.1093/NAR/GKW1014
A case-based discussion of clinical problems in the management of patients treated with ruxolitinib for myelofibrosis.
Publisher: Wiley
Date: 03-2017
DOI: 10.1111/IMJ.13341
Abstract: Ruxolitinib is a dual janus kinase 1 (JAK1)/JAK2 inhibitor used to treat splenomegaly and symptoms associated with myelofibrosis (MF). Current therapeutic options for symptomatic MF include supportive care, myelosuppressive therapy (such as hydroxycarbamide) and janus kinase (JAK) inhibitors (in particular ruxolitinib). Allogeneic stem cell transplantation remains the only potentially curative treatment for MF, and younger transplant-eligible patients should still be considered for allogeneic stem cell transplantation however, this is applicable only to a small proportion of patients. There is now increasing and extensive experience of the efficacy and safety of ruxolitinib in MF, both in clinical trials and in 'real-world' practice. The drug has been shown to be of benefit in intermediate-1 risk patients with symptomatic splenomegaly or other MF-related symptoms, and higher risk disease. Optimal use of the drug is required to maximise clinical benefit, requiring an understanding of the balance between dose-dependent responses and dose-limiting toxicities. There is also increasing experience in the use of ruxolitinib in the pre-transplantation setting. This paper aims to utilise several 'real-life' cases to illustrate several strategies that may help to optimise clinical practice.
High-throughput chromatin information enables accurate tissue-specific prediction of transcription factor binding sites
Publisher: Oxford University Press (OUP)
Date: 06-11-2009
DOI: 10.1093/NAR/GKN866
A high-throughput screening strategy for detecting CRISPR-Cas9 induced mutations using next-generation sequencing
Publisher: Springer Science and Business Media LLC
Date: 2014
Clinical acceleration of JAK2 p.V617F driven myeloproliferative disease due to a new uncommon homozygous MPL p.Y591D mutation
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 04-06-2020
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541164
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy
Publisher: Springer Science and Business Media LLC
Date: 11-11-2021
DOI: 10.1038/S41467-021-26849-W
Abstract: Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.
Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease.
Publisher: Springer Science and Business Media LLC
Date: 22-05-2017
DOI: 10.1038/NG.3871
Erythroid Kruppel-like Factor Regulates the G1 Cyclin Dependent Kinase Inhibitor p18INK4c
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.JMB.2007.02.109
Abstract: Erythroid Kruppel-like factor (EKLF, KLF1) is an essential erythroid cell specific C(2)H(2) zinc finger transcription factor that binds CACC box elements in promoters and distant regulatory elements to activate transcription. Forced expression of EKLF arrests cell ision. The cyclin dependent kinase (Cdk) inhibitor p18(INK4c) was identified as a potential novel EKLF target gene from an expression profiling study. The p18(INK4c) protein functions as an inhibitor of Cdk4 and Cdk6 activity during early G1 phase of the cell cycle, thus acting as a physiological brake on cell ision. We confirmed p18(INK4c) is downregulated in EKLF null mice by real-time PCR and Western blotting, and identified three closely associated and highly conserved EKLF binding sites (CCNCNCCCN) approximately 1 kb upstream of the p18(INK4c) transcriptional start site. We showed that EKLF binds to one of these elements by gel shift assay and demonstrated this site is capable of driving EKLF dependent transcription. We also determined by chromatin immunoprecipitation (ChIP) that this region of the p18(INK4c) promoter is bound by EKLF in erythroid cells. Thus, EKLF is a direct regulator of p18(INK4c) gene expression, and much of EKLF's role in driving erythroid cell differentiation may occur via p18(INK4c).
A global role for EKLF in definitive and primitive erythropoiesis
Publisher: American Society of Hematology
Date: 15-04-2006
DOI: 10.1182/BLOOD-2005-07-2888
Abstract: Erythroid Kruppel-like factor (EKLF, KLF1) plays an important role in definitive erythropoiesis and β-globin gene regulation but failure to rectify lethal fetal anemia upon correction of globin chain imbalance suggested additional critical EKLF target genes. We employed expression profiling of EKLF-null fetal liver and EKLF-null erythroid cell lines containing an inducible EKLF-estrogen receptor (EKLF-ER) fusion construct to search for such targets. An overlapping list of EKLF-regulated genes from the 2 systems included α-hemoglobin stabilizing protein (AHSP), cytoskeletal proteins, hemesynthesis enzymes, transcription factors, and blood group antigens. One EKLF target gene, dematin, which encodes an erythrocyte cytoskeletal protein (band 4.9), contains several phylogenetically conserved consensus CACC motifs predicted to bind EKLF. Chromatin immunoprecipitation demonstrated in vivo EKLF occupancy at these sites and promoter reporter assays showed that EKLF activates gene transcription through these DNA elements. Furthermore, investigation of EKLF target genes in the yolk sac led to the discovery of unexpected additional defects in the embryonic red cell membrane and cytoskeleton. In short, EKLF regulates global erythroid gene expression that is critical for the development of primitive and definitive red cells.
Knockdown of zebrafish crim1 results in a bent tail phenotype with defects in somite and vascular development
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.MOD.2006.01.003
Abstract: The Crim1 gene encodes a transmembrane protein containing six cysteine-rich repeats similar to those found in the BMP antagonist, chordin (chd). To investigate its physiological role, zebrafish crim1 was cloned and shown to be both maternally and zygotically expressed during zebrafish development in sites including the vasculature, intermediate cell mass, notochord, and otic vesicle. Bent or hooked tails with U-shaped somites were observed in 85% of morphants from 12 hpf. This was accompanied by a loss of muscle pioneer cells. While morpholino knockdown of crim1 showed some evidence of ventralisation, including expansion of the intermediate cell mass (ICM), reduction in head size bent tails and disruption to the somites and notochord, this did not mimic the classically ventralised phenotype, as assessed by the pattern of expression of the dorsal markers chordin, otx2 and the ventral markers eve1, pax2.1, tal1 and gata1 between 75% epiboly and six-somites. From 24 hpf, morphants displayed an expansion of the ventral mesoderm-derived ICM, as evidenced by expansion of tal1, lmo2 and crim1 itself. Analysis of the crim1 morphant phenotype in Tg(fli:EGFP) fish showed a clear reduction in the endothelial cells forming the intersegmental vessels and a loss of the dorsal longitudinal anastomotic vessel (DLAV). Hence, the primary role of zebrafish crim1 is likely to be the regulation of somitic and vascular development.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541182.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants
Publisher: American Society of Hematology
Date: 14-04-2016
DOI: 10.1182/BLOOD-2016-01-694331
Abstract: Until recently our approach to analyzing human genetic diseases has been to accurately phenotype patients and sequence the genes known to be associated with those phenotypes for ex le, in thalassemia, the globin loci are analyzed. Sequencing has become increasingly accessible, and thus a larger panel of genes can be analyzed and whole exome and/or whole genome sequencing can be used when no variants are found in the candidate genes. By using such approaches in patients with unexplained anemias, we have discovered that a broad range of hitherto unrelated human red cell disorders are caused by variants in KLF1, a master regulator of erythropoiesis, which were previously considered to be extremely rare causes of human genetic disease.
Fragmentation of tissue-resident macrophages during isolation confounds analysis of single-cell preparations from mouse hematopoietic tissues
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.CELREP.2021.110058
Abstract: Mouse hematopoietic tissues contain abundant tissue-resident macrophages that support immunity, hematopoiesis, and bone homeostasis. A systematic strategy to characterize macrophage subsets in mouse bone marrow (BM), spleen, and lymph node unexpectedly reveals that macrophage surface marker staining emanates from membrane-bound subcellular remnants associated with unrelated cells. Intact macrophages are not present within these cell preparations. The macrophage remnant binding profile reflects interactions between macrophages and other cell types in vivo. Depletion of CD169
Thrombopoietin rescues in vitro erythroid colony formation from mouse embryos lacking the erythropoietin receptor.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-08-1996
Abstract: The interaction of the hormone erythropoietin and its receptor (EpoR) is though to be required for normal hematopoiesis. To define the role of EpoR in this process, the murine EpoR was disrupted by homologous recombination. Mice lacking the EpoR died in utero at embryonic day 11-12.5 with severe anemia. Embryonic erythropoiesis was markedly diminished, while fetal liver hematopoiesis was blocked at the proerythroblast stage. Other cell types known to express EpoR, including megakaryocytes, mast, and neural cells were morphologically normal. Reverse transcription-coupled PCR analysis of RNA from embryonic yolk sac, peripheral blood, and fetal liver demonstrated near normal transcripts levels for EKLF, thrombopoietin (Tpo), c-MPL, GATA-1, GATA-2, and alpha- and embryonic beta H1-globin but non for adult beta maj-globin. While colony-forming unit-erythroid (CFU-E) and burst-forming unit-erythroid (BFU-E) colonies were not present in cultures derived from EpoR-/- liver or yolk sac cells, hemoglobin-containing BFU-E colonies were detected in cultures treated with recombinant Tpo and Kit ligand or with Tpo and interleukin 3 and 11. Rescued BFU-E colonies expressed adult beta-globin and c-MPL and appeared morphologically normal. Thus, erythroid progenitors are formed in vivo in mice lacking the EpoR, and our studies demonstrate that a signal transmitted through the Tpo receptor c-MPL stimulates proliferation and terminal differentiation of these progenitors in vitro.
Zebrafish KLF4 is essential for anterior mesendoderm/pre-polster differentiation and hatching
Publisher: Wiley
Date: 12-10-2005
DOI: 10.1002/DVDY.20571
Abstract: Gene knockout studies of Krüppel-like factors (KLFs) in mice have shown essential roles in organogenesis. A screen for KLF family members in zebrafish identified many KLFs. One of these, zebrafish KLF4 (zKLF4) is the homologue of neptune, a Xenopus laevis KLF. zKLF4 is expressed from approximately 80% epiboly a patch of dorsal/anterior mesendodermal cells called the pre-polster and, subsequently, in the polster and hatching gland. Here we investigate the function of zKLF4 using morpholino-based antisense oligonucleotides. Knockdown of zKLF4 resulted in complete absence of hatching gland formation and subsequent hatching in zebrafish. In addition, there was early knockdown of expression of the pre-polster/anterior mesendoderm markers CatL, cap1, and BMP4. These results indicate zKLF4 is expressed within the pre-polster, an early mesendodermal site, and that it plays a critical role in the differentiation of these cells into hatching gland cells.
Three fingers on the switch
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2013
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541176.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Histone Deacetylase-Dependent Establishment and Maintenance of Broad Low-Level Histone Acetylation within a Tissue-Specific Chromatin Domain
Publisher: American Chemical Society (ACS)
Date: 26-11-2002
DOI: 10.1021/BI026786Q
Abstract: The murine beta-globin locus in adult erythroid cells is characterized by a broad pattern of erythroid-specific histone acetylation. The embryonic beta-globin genes Ey and betaH1 are located in a approximately 30 kb central subdomain characterized by low-level histone acetylation, while the fetal/adult genes betamajor and betaminor and the upstream locus control region reside in hyperacetylated chromatin. Histone deacetylase (HDAC) inhibitors induce H4 acetylation at the Ey promoter [Forsberg, E. C., Downs, K. M., Christensen, H. M., Im, H., Nuzzi, P. A., and Bresnick, E. H. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 14494-14499], indicating that HDACs maintain low-level H4 acetylation at this site. Since little is known about the establishment of broad histone modification patterns, we asked whether this mechanism applies only to the promoter or to the entire subdomain. We show that the HDAC inhibitor trichostatin A induces H4 hyperacetylation at multiple sites within the subdomain in erythroid cells. The hematopoietic factors p45/NF-E2, GATA-1, and erythroid kruppel-like factor (EKLF), which function through cis elements of the beta-globin locus, were not required for induction of H4 hyperacetylation. Analysis of chromatin structure within the subdomain revealed low accessibility to restriction endonucleases and nearly complete CpG dinucleotide methylation. Induction of H4 hyperacetylation did not restore hallmark features of transcriptionally active chromatin. We propose that an HDAC-dependent surveillance mechanism counteracts constitutive histone acetyltransferase (HAT) access, thereby maintaining low-level H4 acetylation throughout the subdomain.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541179
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Isolation and characterization of the cDNA encoding BKLF/TEF-2, a major CACCC-box-binding protein in erythroid cells and selected other cells
Publisher: Informa UK Limited
Date: 04-1996
Abstract: Schizophrenia (SZ) is a mental disorder whereby due to the secretion of specific chemicals in the brain, the function of some brain regions is out of balance, leading to the lack of coordination between thoughts, actions, and emotions. This study provides various intelligent deep learning (DL)-based methods for automated SZ diagnosis
Genetic Variants Within the Erythroid Transcription Factor, KLF1, and Reduction of the Expression of Lutheran and Other Blood Group Antigens: Review of the In(Lu) Phenotype
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.TMRV.2019.01.004
Abstract: Erythroid-specific Krüppel-like factor 1, or KLF1, is an integral transcriptional activator for erythropoiesis. Genetic variants within KLF1 can result in a range of erythropoietic clinical phenotypes from benign to significant. The In(Lu) phenotype refers to changes in the quantitative expression of blood group-associated red cell surface molecules due to KLF1 variants which are otherwise clinically benign. These clinically benign KLF1 variants are associated with a reduced expression of 1 or more red cell membrane proteins/carbohydrates that carry blood group antigens for the LU (Lutheran), IN (Indian), P1PK, LW (Landsteiner-Wiener), KN (Knops), OK, RAPH, and I blood group systems. This is of significance during routine serologic blood typing when expression falls below the test sensitivity and therefore impacts on the ability to accurately detect the presence of affected blood group antigens. This is of clinical importance because the transfusion requirements for in iduals with the In(Lu) phenotype differ from those of in iduals that have a true Lu
Identification of a novel, erythroid BKLF promoter
Publisher: Elsevier BV
Date: 03-2007
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541173
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Generation of Mice Deficient in both KLF3/BKLF and KLF8 Reveals a Genetic Interaction and a Role for These Factors in Embryonic Globin Gene Silencing
Publisher: Informa UK Limited
Date: 08-2013
DOI: 10.1128/MCB.00074-13
Lethal β-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF
Publisher: Springer Science and Business Media LLC
Date: 05-1995
DOI: 10.1038/375318A0
Abstract: Globin genes are regulated in a tissue-specific and developmental stage-specific manner, with the beta-globin gene being the last to be activated in the beta-gene cluster. CACCC-nucleotide sequences, which bind multiple nuclear proteins, including ubiquitously expressed Sp1 and erythroid Krüppel-like factor (EKLF), are among the cis-regulatory sequences critical for transcription of globin and non-globin erythroid-expressed genes. To determine the function of EKLF in vivo, we created mice deficient in EKLF by gene targeting. These embryos die of anaemia during fetal liver erythropoiesis and show the molecular and haematological features of beta-globin deficiency, found in beta-thalassaemia. Although it is expressed at all stages, EKLF is not required for yolk sac erythropoiesis, erythroid commitment or expression of other potential target genes. Its stage-specific and beta-globin-gene-specific requirement suggests that EKLF may facilitate completion of the fetal-to-adult (haemoglobin gamma to beta) switch in humans.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541170
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
A mechanism for Ikaros regulation of human globin gene switching
Publisher: Wiley
Date: 09-04-2008
DOI: 10.1111/J.1365-2141.2008.07065.X
Abstract: The human beta globin locus consists of an upstream LCR and functional genes arranged sequentially in the order of their expression during development: 5'-HBE1, HBG2, HBG1, HBD, HBB-3'. Haemoglobin switching entails the successive recruitment of these genes into an active chromatin hub (ACH). Here we show that the transcription factor Ikaros plays a major role in the formation of the beta-globin ACH, and in haemoglobin switching. In Plastic mice, where the DNA-binding region of Ikaros is disrupted by a point mutation, there is concomitant marked down-regulation of HBB, and up-regulation of HBG expression. We show for the first time Ikaros and its family member Eos, bind to critical cis elements implicated in haemoglobin switching and deletional hereditary persistence of fetal haemoglobin (HPFH). Chromatin conformation capture (3C) data demonstrated that Ikaros facilitates long-distance DNA looping between the LCR and a region upstream of HBD. This study provides new insights into the mechanism of stage-specific assembly of the beta-globin ACH, and HPFH.
Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541176
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
EKLF/KLF1 controls cell cycle entry via direct regulation of E2f2
Publisher: Elsevier BV
Date: 07-2009
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