ORCID Profile
0000-0002-4915-4612
Current Organisation
University of South Australia
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Publisher: Springer Science and Business Media LLC
Date: 29-03-2019
Publisher: Wiley
Date: 12-2013
DOI: 10.1002/IUB.1233
Abstract: The mechanisms by which cells control their growth and behavioral identities are complex and require adaptability to environmental changes. Transcription factors act as master controllers of many of these pivotal points through their ability to influence the expression of many thousands of downstream genes, and increasingly research is showing that transcription factor regulation of target genes can change in response to environmental stimuli and cell type such that their function is not prescribed but rather context-dependent. Krüppel like factor 5 (KLF5) is an ex le of such a transcription factor, where evidence of disparate effects on cell growth and differentiation in normal and transformed tissue are clear. Here we present and discuss the literature covering the differential roles of KLF5 in particular tissues and cancer states, and the mechanisms by which these differences are effected through the regulation of KLF5 protein function in response to different cellular states and the direct effect on target gene expression.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 29-09-2017
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.LEUKRES.2017.02.010
Abstract: miR-155 has emerged as one of the key microRNAs (miRNAs) involved in normal and malignant myelopoiesis, and high expression of this miRNA has been flagged as a strong independent prognostic marker in Acute Myeloid Leukemia (AML). While elevated expression of miR-155 has been associated with FLT3-ITD mutations, other mechanisms which may regulate expression of this miRNA in AML remain largely unknown. Here, we present new evidence that miR-155 may be a prime target of IL-3 signaling in primary AML cells. This finding, together with the increasingly apparent role for miR-155 in oncogenesis, and the upregulation of the IL-3 receptor alpha subunit in AML, lead us to propose this pathway may significantly contribute to the leukemic transformation.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2013
DOI: 10.1038/LEU.2013.47
Publisher: Springer Science and Business Media LLC
Date: 12-02-2021
Publisher: Informa UK Limited
Date: 18-01-2012
DOI: 10.3109/08977194.2011.649919
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pluripotent cytokine produced by many cells in the body, which regulates normal and malignant hemopoiesis as well as innate and adaptive immunity. GM-CSF assembles and activates its heterodimeric receptor complex on the surface of myeloid cells, initiating multiple signaling pathways that control key functions such as cell survival, cell proliferation, and functional activation. Understanding the molecular composition of these pathways, the interaction of the various components as well as the kinetics and dose-dependent mechanics of receptor activation provides valuable insights into the function of GM-CSF as well as the related cytokines, interleukin-3 and interleukin-5. This knowledge provides opportunities for the development of new therapies to block the action of these cytokines in hematological malignancy and chronic inflammation.
Publisher: Wiley
Date: 28-11-2012
DOI: 10.1111/BJH.12131
Publisher: Elsevier BV
Date: 2011
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2019
DOI: 10.1158/2159-8290.23854361
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2018
DOI: 10.1038/LEU.2017.196
Publisher: Springer Science and Business Media LLC
Date: 14-05-2019
DOI: 10.1038/S41375-019-0479-8
Abstract: Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with "Very low" or "Low" Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.
Publisher: Oxford University Press (OUP)
Date: 05-03-2014
Abstract: Aberrant activation of β-catenin is a common event in AML and is an independent predictor of poor prognosis. Although increased β-catenin signaling in AML has been associated with oncogenic translocation products and activating mutations in the FLT3R, the mechanisms that activate β-catenin in AML more broadly are still unclear. Here, we describe a novel link between IL-3 signaling and the regulation of β-catenin in myeloid transformation and AML. In a murine model of HoxB8 and IL-3 cooperation, we show that β-catenin protein levels are modulated by IL-3 and that Cre-induced deletion of β-catenin abolishes IL-3-dependent growth and colony formation. In IL-3-dependent leukemic TF-1.8 cells, we observed increased β-catenin protein levels and nuclear localization in response to IL-3, and this correlated with transcriptional induction of β-catenin target genes. Furthermore, IL-3 promoted β-catenin accumulation in a subset of AML patient s les, and gene-expression profiling of these cells revealed induction of WNT/β-catenin and TCF4 gene signatures in an IL-3-dependent manner. This study is the first to link β-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of β-catenin activity in some patients with AML.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854361.V1
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2016
DOI: 10.1038/BCJ.2016.70
Publisher: Springer Science and Business Media LLC
Date: 06-1201
Publisher: American Society of Hematology
Date: 30-06-2022
Abstract: Inducing cell death by the sphingolipid ceramide is a potential anticancer strategy, but the underlying mechanisms remain poorly defined. In this study, triggering an accumulation of ceramide in acute myeloid leukemia (AML) cells by inhibition of sphingosine kinase induced an apoptotic integrated stress response (ISR) through protein kinase R–mediated activation of the master transcription factor ATF4. This effect led to transcription of the BH3-only protein Noxa and degradation of the prosurvival Mcl-1 protein on which AML cells are highly dependent for survival. Targeting this novel ISR pathway, in combination with the Bcl-2 inhibitor venetoclax, synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anticancer effects of ceramide and preclinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.
Publisher: Springer Science and Business Media LLC
Date: 15-11-2020
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.CCELL.2020.05.014
Abstract: Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC) pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positive modulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewal genes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stem cell growth factors to block differentiation and promote proliferation of primary AML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works through cooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interaction by clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts but does not affect normal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependent leukemia.
Publisher: Royal Society of Chemistry (RSC)
Date: 1999
DOI: 10.1039/A809571J
Publisher: American Society of Hematology
Date: 20-06-2017
DOI: 10.1182/BLOODADVANCES.2016002931
Abstract: High CD123 expression increases proliferation and results in enhanced survival in response to low concentration of IL-3 in vitro. High CD123-expressing LSCs downregulate chemokine receptor expression, affecting niche interactions.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854346.V1
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: Wiley
Date: 22-08-2011
Publisher: Springer Science and Business Media LLC
Date: 08-01-2009
DOI: 10.1038/LEU.2008.349
Abstract: The tumor suppressor Gadd45alpha was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45alpha as a downregulated gene in response to constitutive signaling from two FLT3 mutants (FLT3-ITD and FLT3-TKD) commonly found in AML, and a leukemogenic GM-CSF receptor trans-membrane mutant (GMR-V449E). GADD45A mRNA downregulation is also associated with FLT3-ITD(+) AML. Sustained ERK1/2 signaling contributes significantly to receptor-mediated downregulation of Gadd45alpha mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD(+) cell line MV4 . Knockdown of Gadd45alpha with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45alpha in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45alpha overexpression in FLT3-ITD(+) AML cell lines also resulted in reduced growth associated with increased apoptosis and G(1)/S cell cycle arrest. Overexpression of Gadd45alpha in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45alpha downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45alpha by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709852
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/2159-8290.CD-22-1396
Abstract: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. This article is highlighted in the In This Issue feature, p. 1749
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854355.V1
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: American Society of Hematology
Date: 03-12-2015
DOI: 10.1182/BLOOD.V126.23.1365.1365
Abstract: The Acute Myeloid Leukemia (AML) subtype characterised by translocations of the Mixed-Lineage Leukemia gene, MLL (t11q23 MLL-AML), is a particularly devastating disease with a median overall survival of only 9 months with current standard therapy. Cyclin dependent kinase (CDK) 9 inhibitors (CDK9i) directly target the CDK9/cyclin T complex (pTEFb) that is essential for activity of the MLL-fusion proteins and for transcriptional elongation, and therefore leads to reduction of transcript levels for multiple key leukemic oncogenes e.g. HOXA9, MYC and MCL1. Several observations suggest that utilising CDK9i to simultaneously target these oncogenes will be an effective strategy for AML, and MLL-AML in particular: (i) Leukemic stem cell (LSC) fractions of AML cells express a high level of MCL1, (ii) Targeting MCL1 has been demonstrated to reduce leukaemia cell survival in a murine model of MLL-ENL, (iii) MCL1 is consistently elevated in AML patients at relapse, (iv) HOXA9 is critical for leukemogenesis in many AMLs, in particular MLL-AML, (v) MYC has been shown to be a critical oncogene in MLL-AML, and (vi) CDK9 function has been shown to be important for MYC-driven tumorigenesis. Our in vitro and in vivo data support the clinical potential of a novel orally bioavailable inhibitor of CDK9, CDKI-73, as an effective therapy for MLL-AML patients. CDKI-73 is a potent inhibitor of CDK9 (Ki 3.5nM)1 and has been shown to induce down-regulation of MCL1, and cell death of Chronic Lymphocytic Leukemia (CLL) B-cells2 and Ovarian Cancer (OvCa) cells3 with nanomolar potency. At doses that are highly toxic for tumour cells, CDKI-73 shows limited toxicity for normal T- and B- Lymphocytes, Bone Marrow Mononuclear cells (BMMNC) and normal colony forming cells (CFC) from the BMMNC fraction. CDKI-73 has many favorable properties also making it an excellent clinical candidate for AML when compared to other CDK9i in particular, CDKI-73 is (i) unique in its spectrum of inhibition, including targeting CDK6 (IC50 = 0.038 µM a critical kinase for MLL-AML4), and is (ii) orally bioavailable (F = 56%)2, facilitating sustained in vivo target inhibition. Here we present data showing that in MLL-AML cell lines, CDKI-73 induces growth suppression and apoptosis associated with rapid loss of Myc and MCL1, and activation of PARP. In primary AML patient s les treated with 200nM CDKI-73, we have observed a similar decrease in MCL1 protein levels, with increased 7AAD uptake and Annexin-V staining, consistent with apoptotic cell death. Using a subcutaneous MV4 nude mouse xenograft model, we have shown that oral dosing of CDKI-73 (100 mg/kg once every 3 days for 18 days) resulted in a high level of anti-tumour efficacy (p .0001 compared to vehicle-treated mice), with minimal toxicity. Moreover, for an established MLL-AML patient-derived xenograft (PDX) generated in NOD/SCID-IL2RG-/- (NSG) mice we also observed significant inhibition of human AML in peripheral blood (p .0001), BM (p .05) and spleen (p .001) with administration of CDKI-73 at 75 mg/kg every 3 days for 15 days. In both models CDKI-73 was well-tolerated at these doses, consistent with our published and preliminary data showing differential effects of CDKI-73 on tumour versus normal cell populations. Given this data, our priority now is to establish the effectiveness of CDKI-73 across a larger panel of primary MLL-AML s les, in further patient derived AML xenografts, and as a combination treatment with AML chemotherapy. REFERENCES: 1. Shao H, Shi S, et al. (2013). J Med Chem. 56(3):640-59. 2. Walsby E, Pratt G, et al. (2014). Oncotarget. 5(2):375-85. 3. Lam F, Abbas AY, et al. (2014). Oncotarget. 5(17):7691-704. 4. Placke T, Faber K, et al. (2014). Blood. 124(1):13-23. No relevant conflicts of interest to declare.
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.CYTOGFR.2009.01.002
Abstract: Hematopoietic growth factor (HGF) mimetics offer a number of attractive advantages as therapeutic agents. Small chemical compounds, in particular, provide reduced cost and oral availability. As many of these mimetics are unrelated in structure to the normal cytokine the immunogenic response is not a significant issue. Isolation of small peptide agonists for erythropoietin (EPO) and thrombopoietin (TPO) receptors has been associated with significant translational challenges and here we summarize approaches used to achieve the potency and stability required for clinical utility. We also compare and contrast the initial screening approaches, and the translational and clinical issues associated with two recently approved TPO mimetics, romiplostim and the orally available eltrombopag. Finally we summarize the development and clinical findings for the EPO mimetic, Hematide, consider alternative approaches, and discuss the future potential for isolation of growth factor (GF) mimetics.
Publisher: Wiley
Date: 20-02-2011
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709858
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2022
DOI: 10.1038/S41467-022-30223-9
Abstract: The interaction of germline variation and somatic cancer driver mutations is under-investigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondrially-encoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 ( IDH1 ), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1 -mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709855
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2012
DOI: 10.1038/BJC.2012.173
Publisher: American Association for Cancer Research (AACR)
Date: 02-2013
DOI: 10.1158/0008-5472.CAN-13-2424
Abstract: Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic lification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 lification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists. Cancer Res 74(3) 921–31. ©2013 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709873.V1
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: American Society of Hematology
Date: 09-02-2017
DOI: 10.1182/BLOOD-2016-06-720433
Abstract: Inhibition of SPHK1 in human AML cells induces MCL1 degradation and caspase-dependent cell death. SPHK1 inhibitors reduce leukemic burden and prolong survival in orthotopic patient-derived xenografts of AML.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2010
DOI: 10.1038/LEU.2010.85
Publisher: MDPI AG
Date: 15-08-2023
Abstract: Nanoparticle-based therapeutics are being clinically translated for treating cancer. Even when thought to be biocompatible, nanoparticles are being increasingly identified as altering cell regulation and homeostasis. Antioxidant pathways are important for maintaining cell redox homeostasis and play important roles by maintaining ROS levels within tolerable ranges. Here, we sought to understand how a model of a relatively inert nanoparticle without any therapeutic agent itself could antagonize a cancer cell lines’ antioxidant mechanism. A label-free protein expression approach was used to assess the glutathione-thioredoxin antioxidative pathway in a prostate cancer cell line (PC-3) after exposure to gold nanoparticles conjugated with a targeting moiety (transferrin). The impact of the nanoparticles was also corroborated through morphological analysis with TEM and classification of pro-apoptotic cells by way of the sub-G0/G1 population via the cell cycle and annexin V apoptosis assay. After a two-hour exposure to nanoparticles, major proteins associated with the glutathione-thioredoxin antioxidant pathway were downregulated. However, this response was acute, and in terms of protein expression, cells quickly recovered within 24 h once nanoparticle exposure ceased. The impact on PRDX-family proteins appears as the most influential factor in how these nanoparticles induced an oxidative stress response in the PC-3 cells. An apparent adaptive response was observed if exposure to nanoparticles continued. Acute exposure was observed to have a detrimental effect on cell viability compared to continuously exposed cells. Nanoparticle effects on cell regulation likely provide a compounding therapeutic advantage under some circumstances, in addition to the action of any cytotoxic agents however, any therapeutic advantage offered by nanoparticles themselves with regard to vulnerabilities specific to the glutathione-thioredoxin antioxidative pathway is highly temporal.
Publisher: Springer Science and Business Media LLC
Date: 06-05-2021
DOI: 10.1038/S41388-021-01800-X
Abstract: Transcription factor MYB has recently emerged as a promising drug target for the treatment of acute myeloid leukemia (AML). Here, we have characterized a group of natural sesquiterpene lactones (STLs), previously shown to suppress MYB activity, for their potential to decrease AML cell proliferation. Unlike what was initially thought, these compounds inhibit MYB indirectly via its cooperation partner C/EBPβ. C/EBPβ-inhibitory STLs affect the expression of a large number of MYB-regulated genes, suggesting that the cooperation of MYB and C/EBPβ broadly shapes the transcriptional program of AML cells. We show that expression of GFI1 , a direct MYB target gene, is controlled cooperatively by MYB, C/EBPβ, and co-activator p300, and is down-regulated by C/EBPβ-inhibitory STLs, exemplifying that they target the activity of composite MYB-C/EBPβ-p300 transcriptional modules. Ectopic expression of GFI1, a zinc-finger protein that is required for the maintenance of hematopoietic stem and progenitor cells, partially abrogated STL-induced myelomonocytic differentiation, implicating GFI1 as a relevant target of C/EBPβ-inhibitory STLs. Overall, our data identify C/EBPβ as a pro-leukemogenic factor in AML and suggest that targeting of C/EBPβ may have therapeutic potential against AML.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2016
DOI: 10.1038/NM.4125
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854352.V1
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709849
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.CYTOGFR.2013.03.002
Abstract: The GM-CSF, IL-3 and IL-5 family of cytokines, also known as the βc family due to their receptors sharing the signalling subunit βc, regulates multiple biological processes such as native and adaptive immunity, inflammation, normal and malignant hemopoieis, and autoimmunity. Australian scientists played a major role in the discovery and biological characterisation of the βc cytokines and their recent work is revealing unique features of cytokine receptor assembly and signalling. Furthermore, specific antibodies have been generated to modulate their function. Characterisation of the structural and dynamic requirements for the activation of the βc receptor family and the molecular definition of downstream signalling pathways are providing new insights into cytokine receptor signalling as well as new therapeutic opportunities.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Springer Science and Business Media LLC
Date: 13-07-2013
DOI: 10.1038/LEU.2012.193
Publisher: Springer Science and Business Media LLC
Date: 04-09-2011
DOI: 10.1038/NG.913
Publisher: Springer Science and Business Media LLC
Date: 26-05-2017
DOI: 10.1038/S41598-017-02655-7
Abstract: We describe a novel ERBB1/EGFR somatic mutation (p. C329R c.985 T C) identified in a patient with JAK2 V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFR C329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2 V617F -positive clone in this PV patient harbors EGFR C329R , thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN s les, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2 V617F disease clone in MPN.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709849.V1
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854334
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854331
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2012
DOI: 10.1038/LEU.2012.346
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854325.V1
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709855.V1
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: American Association for Cancer Research (AACR)
Date: 30-08-2012
DOI: 10.1158/0008-5472.CAN-12-1832
Abstract: Patients diagnosed with leukemia approach their treatment with the hope of cure despite the effect on their quality of life. Some patients will be cured, others will die from treatment, and some will die of their disease. A common theme at the New Directions in Leukemia Research (NDLR 2012) meeting was that cure will come if the drivers of the disease are better understood. Key messages included the power of combination platforms to understand the genetic and epigenetic modifications in leukemia to enable development of rational therapies, which can be tested via new clinical trial designs ensuring rapid clinical implementation. Cancer Res 72(17) 4300–3. ©2012 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709870.V1
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: Springer Science and Business Media LLC
Date: 04-2013
DOI: 10.1186/1471-2105-14-S5-S10
Abstract: DNA methylation profiling reveals important differentially methylated regions (DMRs) of the genome that are altered during development or that are perturbed by disease. To date, few programs exist for regional analysis of enriched or whole-genome bisulfate conversion sequencing data, even though such data are increasingly common. Here, we describe an open-source, optimized method for determining empirically based DMRs (eDMR) from high-throughput sequence data that is applicable to enriched whole-genome methylation profiling datasets, as well as other globally enriched epigenetic modification data. Here we show that our bimodal distribution model and weighted cost function for optimized regional methylation analysis provides accurate boundaries of regions harboring significant epigenetic modifications. Our algorithm takes the spatial distribution of CpGs into account for the enrichment assay, allowing for optimization of the definition of empirical regions for differential methylation. Combined with the dependent adjustment for regional p-value combination and DMR annotation, we provide a method that may be applied to a variety of datasets for rapid DMR analysis. Our method classifies both the directionality of DMRs and their genome-wide distribution, and we have observed that shows clinical relevance through correct stratification of two Acute Myeloid Leukemia (AML) tumor sub-types. Our weighted optimization algorithm eDMR for calling DMRs extends an established DMR R pipeline (methylKit) and provides a needed resource in epigenomics. Our method enables an accurate and scalable way of finding DMRs in high-throughput methylation sequencing experiments. eDMR is available for download at /edmr/ .
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709873
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709870
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709858.V1
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709861.V1
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854334.V1
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Association for Cancer Research (AACR)
Date: 20-08-0006
DOI: 10.1158/2159-8290.23854328.V1
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: MDPI AG
Date: 11-02-2019
DOI: 10.3390/IJMS20030749
Abstract: It is evident that regions within tumors are deprived of oxygen, which makes the microenvironment hypoxic. Cancer cells experiencing hypoxia undergo metabolic alterations and cytoprotective adaptive mechanisms to survive such stringent conditions. While such mechanisms provide potential therapeutic targets, the mechanisms by which hypoxia regulates adaptive responses—such as ER stress response, unfolded protein response (UPR), anti-oxidative responses, and autophagy—remain elusive. In this review, we summarize the complex interplay between hypoxia and the ER stress signaling pathways that are activated in the hypoxic microenvironment of the tumors.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2010
DOI: 10.1038/LEU.2009.299
Abstract: In chronic myeloid leukemia (CML) cell lines, brief exposure to pharmacologically relevant dasatinib concentrations results in apoptosis. In this study, we assess the impact of intensity and duration of Bcr-Abl kinase inhibition on primary CD34(+) progenitors of chronic phase CML patients. As CML cells exposed to dasatinib in vivo are in a cytokine-rich environment, we also assessed the effect of cytokines (six growth factors cocktail or granulocyte-macrophage colony-stimulating factor (CSF) or granulocyte-CSF) in combination with dasatinib. In the presence of cytokines, short-term intense Bcr-Abl kinase inhibition (>or=90% p-Crkl inhibition) with 100 nM dasatinib did not reduce CD34(+) colony-forming cells (CFCs). In contrast, without cytokines, short-term exposure to dasatinib reduced CML-CD34(+) CFCs by 70-80%. When cytokines were added immediately after short-term exposure to dasatinib, CML-CD34(+) cells remained viable, suggesting that oncogene dependence of these cells can be overcome by concomitant or subsequent exposure to cytokines. Additional inhibition of Janus tyrosine kinase (Jak) activity re-established the sensitivity of CML progenitors to intense Bcr-Abl kinase inhibition despite the presence of cytokines. These findings support the contention that therapeutic strategies combining intense Bcr-Abl kinase inhibition and blockade of cytokine signaling pathways can be effective for eradication of CML progenitors.
Publisher: American Society of Hematology
Date: 22-04-2010
DOI: 10.1182/BLOOD-2009-08-235846
Abstract: Granulocyte/macrophage colony-stimulating factor promotes growth, survival, differentiation, and activation of normal myeloid cells and plays an important role in myeloid leukemias. The GM-CSF receptor (GMR) shares a signaling subunit, βc, with interleukin-3 and interleukin-5 receptors and has recently been shown to induce activation of Janus kinase 2 (JAK2) and downstream signaling via formation of a unique dodecameric receptor complex. In this study we use 2 activated βc mutants that display distinct signaling capacity and have differential requirements for the GMR α-subunit (GMR-α) to dissect the signaling pathways associated with the GM-CSF response. The V449E transmembrane mutant selectively activates JAK2/signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) pathways, resulting in a high level of sensitivity to JAK and ERK inhibitors, whereas the extracellular mutant (FIΔ) selectively activates the phosphoinositide 3-kinase/Akt and IκKβ/nuclear factorκB pathways. We also demonstrate a novel and direct interaction between the SH3 domains of Lyn and Src with a conserved proline-rich motif in GMR-α and show a selective requirement for Src family kinases by the FIΔ mutant. We relate the nonoverlapping nature of signaling by the activated mutants to the structure of the unique GMR complex and propose alternative modes of receptor activation acting synergistically in the mature liganded receptor complex.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709867.V1
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2021
DOI: 10.1038/S41375-021-01246-W
Abstract: The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline s les of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9% p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5% p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.
Publisher: American Society of Hematology
Date: 07-07-2016
DOI: 10.1182/BLOOD-2015-12-684514
Abstract: Klf5 functions in hematopoiesis to regulate HSC and progenitor proliferation and localization in the bone marrow. Klf5 is required in the granulocyte lineage and positively affects neutrophil output at the expense of eosinophil production.
Publisher: American Society of Hematology
Date: 24-03-2020
DOI: 10.1182/BLOODADVANCES.2019000901
Abstract: First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709864
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709861
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709864.V1
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854340.V1
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: American Society of Hematology
Date: 02-12-2021
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854328
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709867
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: Wiley
Date: 02-05-2017
DOI: 10.1111/BJH.14126
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854325
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.C.6749895.V2
Abstract: Abstract Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the in idual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Significance: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-8-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1749 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.C.6749895.V1
Abstract: Abstract Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the in idual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Significance: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854355
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854352
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2022
Publisher: Proceedings of the National Academy of Sciences
Date: 10-09-2010
Abstract: Recent data indicate that a variety of regulatory molecules active in embryonic development may also play a role in the regulation of early hematopoiesis. Here we report that the human Vent-like homeobox gene VENTX , a putative homolog of the Xenopus xvent2 gene, is a unique regulatory hematopoietic gene that is aberrantly expressed in CD34 + leukemic stem-cell candidates in human acute myeloid leukemia (AML). Quantitative RT–PCR documented expression of the gene in lineage positive hematopoietic subpopulations, with the highest expression in CD33 + myeloid cells. Notably, expression levels of VENTX were negligible in normal CD34 + /CD38 − or CD34 + human progenitor cells. In contrast to this, leukemic CD34 + /CD38 − cells from AML patients with translocation t(8,21) and normal karyotype displayed aberrantly high expression of VENTX . Gene expression and pathway analysis demonstrated that in normal CD34 + cells enforced expression of VENTX initiates genes associated with myeloid development and down-regulates genes involved in early lymphoid development. Functional analyses confirmed that aberrant expression of VENTX in normal CD34 + human progenitor cells perturbs normal hematopoietic development, promoting generation of myeloid cells and impairing generation of lymphoid cells in vitro and in vivo. Stable knockdown of VENTX expression inhibited the proliferation of human AML cell lines. Taken together, these data extend our insights into the function of embryonic mesodermal factors in human postnatal hematopoiesis and indicate a role for VENTX in normal and malignant myelopoiesis.
Publisher: Massachusetts Medical Society
Date: 27-07-2000
Publisher: Springer Science and Business Media LLC
Date: 09-02-2016
DOI: 10.1038/LEU.2016.24
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.LEUKRES.2011.09.013
Abstract: Krüppel-like factor 5 (KLF5) has been implicated as a tumor suppressor in various solid tumors such as breast and prostate, and recent studies have demonstrated a role for this protein in neutrophil differentiation of acute promyelocytic leukemia cells in response to ATRA. Here, we show that KLF5 expression increases during primary granulocyte differentiation and that expression of KLF5 is a requirement for granulocyte differentiation of 32D cells. In AML, we show that KLF5 mRNA expression levels are reduced in multiple French-American-British subtypes compared to normal controls, and also in leukemic stem cells relative to normal hematopoietic stem cells. We demonstrate that in selected AML cases, reduced expression is associated with hypermethylation of the KLF5 locus in the proximal promoter and/or intron 1, suggesting that this may represent a Class II genetic lesion in the development of AML.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.C.6749895
Abstract: Abstract Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the in idual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Significance: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-8-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1749 /a /i /
Publisher: Impact Journals, LLC
Date: 15-09-2013
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854346
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: Bioscientifica
Date: 06-2012
DOI: 10.1530/ERC-11-0210
Publisher: Springer Science and Business Media LLC
Date: 12-2016
Abstract: The apoptotic cysteine protease caspase-2 has been shown to suppress tumourigenesis in mice and its reduced expression correlates with poor prognosis in some human malignancies. Caspase-2-deficient mice develop normally but show ageing-related traits and, when challenged by oncogenic stimuli or certain stress, show enhanced tumour development, often accompanied by extensive aneuploidy. As stem cells are susceptible to acquiring age-related functional defects because of their self-renewal and proliferative capacity, we examined whether loss of caspase-2 promotes such defects with age. Using young and aged Casp2 −/− mice, we demonstrate that deficiency of caspase-2 results in enhanced aneuploidy and DNA damage in bone marrow (BM) cells with ageing. Furthermore, we demonstrate for the first time that caspase-2 loss results in significant increase in immunophenotypically defined short-term haematopoietic stem cells (HSCs) and multipotent progenitors fractions in BM with a skewed differentiation towards myeloid progenitors with ageing. Caspase-2 deficiency leads to enhanced granulocyte macrophage and erythroid progenitors in aged mice. Colony-forming assays and long-term culture-initiating assay further recapitulated these results. Our results provide the first evidence of caspase-2 in regulating HSC and progenitor differentiation, as well as aneuploidy, in vivo .
Publisher: Wiley
Date: 25-03-2013
DOI: 10.1111/BJH.12295
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854340
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709852.V1
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: American Society of Hematology
Date: 25-02-2016
DOI: 10.1182/BLOOD-2015-10-676098
Abstract: Novel missense germ line DDX41 mutations define an earlier age of onset of hematologic malignancies than loss-of-function alleles. Carriers of DDX41 germ line mutations usually have normal blood counts until a myeloid or lymphoid malignancy develops.
Publisher: The American Association of Immunologists
Date: 15-07-2010
Abstract: The transcription factor FOXP3 is essential for the formation and function of regulatory T cells (Tregs), and Tregs are essential for maintaining immune homeostasis and tolerance. This is demonstrated by a lethal autoimmune defect in mice lacking Foxp3 and in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome patients. However, little is known about the molecular basis of human FOXP3 function or the relationship between direct and indirect targets of FOXP3 in human Tregs. To investigate this, we have performed a comprehensive genome-wide analysis for human FOXP3 target genes from cord blood Tregs using chromatin immunoprecipitation array profiling and expression profiling. We have identified 5579 human FOXP3 target genes and derived a core Treg gene signature conserved across species using mouse chromatin immunoprecipitation data sets. A total of 739 of the 5579 FOXP3 target genes were differentially regulated in Tregs compared with Th cells, thus allowing the identification of a number of pathways and biological functions overrepresented in Tregs. We have identified gene families including cell surface molecules and microRNAs that are differentially expressed in FOXP3+ Tregs. In particular, we have identified a novel role for peptidase inhibitor 16, which is expressed on the cell surface of & % of resting human CD25+FOXP3+ Tregs, suggesting that in conjunction with CD25 peptidase inhibitor 16 may be a surrogate surface marker for Tregs with potential clinical application.
Publisher: Springer Science and Business Media LLC
Date: 04-07-2018
DOI: 10.1038/LEU.2017.210
Abstract: Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in acute myeloid leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic non-coding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyze transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA genes are located in close proximity to hematopoietic coding genes and show strong expression correlations in AML, (iii) lincRNA gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomize survival in European Leukemia Net (ELN) risk groups and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML.
Publisher: Oxford University Press (OUP)
Date: 22-12-2008
DOI: 10.1189/JLB.1008620
Abstract: Adult stem cells are capable of generating all of the cells of the hematopoietic system, and this process is orchestrated in part by the interactions between these cells and the stroma. T cell progenitors emerge from the stem cell compartment and migrate to the thymus, where their terminal differentiation and maturation occur, and it is during this phase that selection shapes the immune repertoire. Notch ligands, including Delta-like 1 (DL1), play a critical role in this lymphoid differentiation. To mimic this in vitro, stroma-expressing DL1 have been used to generate CD4+CD8+ double-positive and single-positive T cells from hematopoietic stem rogenitor cells. This system provides a robust tool to investigate thymopoiesis however, its capacity to generate regulatory T cells (Tregs) has yet to be reported. Natural Tregs (nTregs) develop in the thymus and help maintain immune homeostasis and have potential clinical use as a cell therapy for modulation of autoimmune disease or for transplant tolerization. Here, we describe for the first time the development of a population of CD4+CD25+ CD127loFoxP3+ cells that emerge in coculture of cord blood (CB) CD34+ progenitors on OP9-DL1 stroma. These hematopoietic progenitor-derived CD4+CD25+ Tregs have comparable suppressor function with CB nTregs in vitro. The addition of IL-2 to the coculture enhanced the expansion and survival of this population significantly. This manipulable culture system, therefore, generates functional Tregs and provides a system to elucidate the mechanism of Treg development.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2015
DOI: 10.1038/LEU.2015.67
Publisher: Portico
Date: 2010
DOI: 10.4137/CMRT.S4334
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854331.V1
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2014
DOI: 10.1038/BCJ.2013.68
Abstract: Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m 2 subcutaneously (days 1–5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.PATHOL.2022.05.015
Abstract: The identification of a somatic mutation associated with myeloid malignancy is of diagnostic importance in myeloproliferative neoplasms (MPNs). In iduals with no mutation detected in common screening tests for variants in JAK2, CALR, and MPL are described as 'triple-negative' and pose a diagnostic challenge if there is no other evidence of a clonal disorder. To identify potential drivers that might explain the clinical phenotype, we used an extended sequencing panel to characterise a cohort of 44 previously diagnosed triple-negative MPN patients for canonical mutations in JAK2, MPL and CALR at low variant allele frequency (found in 4/44 patients), less common variants in the JAK-STAT signalling pathway (12 patients), or other variants in recurrently mutated genes from myeloid malignancies (18 patients), including hotspot variants of potential clinical relevance in eight patients. In one patient with thrombocytosis we identified biallelic germline MPL variants. Neither MPL variant was activating in cell proliferation assays, and one of the variants was not expressed on the cell surface, yet co-expression of both variants led to thrombopoietin hypersensitivity. Our results highlight the clinical value of extended sequencing including germline variant analysis and illustrate the need for detailed functional assays to determine whether rare variants in JAK2 or MPL are pathogenic.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2008
Publisher: Proceedings of the National Academy of Sciences
Date: 19-01-2012
Abstract: Ecotropic viral integration site 1 (EVI1) is an oncogenic dual domain zinc finger transcription factor that plays an essential role in the regulation of hematopoietic stem cell renewal, and its overexpression in myeloid leukemia and epithelial cancers is associated with poor patient survival. Despite the discovery of EVI1 in 1988 and its emerging role as a dominant oncogene in various types of cancer, few EVI1 target genes are known. This lack of knowledge has precluded a clear understanding of exactly how EVI1 contributes to cancer. Using a combination of ChIP-Seq and microarray studies in human ovarian carcinoma cells, we show that the two zinc finger domains of EVI1 bind to DNA independently and regulate different sets of target genes. Strikingly, an enriched fraction of EVI1 target genes are cancer genes or genes associated with cancer. We also show that more than 25% of EVI1-occupied genes contain linked EVI1 and activator protein (AP)1 DNA binding sites, and this finding provides evidence for a synergistic cooperative interaction between EVI1 and the AP1 family member FOS in the regulation of cell adhesion, proliferation, and colony formation. An increased number of dual EVI1/AP1 target genes are also differentially regulated in late-stage ovarian carcinomas, further confirming the importance of the functional cooperation between EVI1 and FOS. Collectively, our data indicate that EVI1 is a multipurpose transcription factor that synergizes with FOS in invasive tumors.
No related grants have been discovered for Richard D'Andrea.