ORCID Profile
0000-0003-1536-5611
Current Organisations
Universidade de Lisboa Faculdade de Ciências
,
Universidade Técnica de Lisboa Instituto Superior Técnico
,
Monash University
,
iCamuno Biotherapeutics
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Chemical sciences | Mathematical sciences | Mathematical physics | Theoretical and computational chemistry
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Publisher: American Society of Hematology
Date: 16-02-2018
DOI: 10.1182/BLOODADVANCES.2017013243
Abstract: Overexpression of Hhex transcription factor blocks myeloid differentiation at the promyelocyte stage. Hhex cooperates with growth factor independence to elicit rapid promyelocytic leukemia in mice.
Publisher: Elsevier BV
Date: 10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 12-2010
DOI: 10.1158/1078-0432.CCR-10-0440
Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is commonly caused by the overexpression of oncogenic transcription factors in developing T cells. In a mouse model of one such oncogene, LMO2, the cellular effect is to induce self-renewal of committed T cells in the thymus, which persist long-term while acquiring additional mutations and eventually giving rise to leukemia. These precancerous stem cells (pre-CSC) are intrinsically resistant to radiotherapy, implying that they may be refractory to conventional cancer therapies. However, they depend on an aberrantly expressed stem cell–like self-renewal program for their maintenance, in addition to a specialized thymic microenvironmental niche. Here, we discuss potential approaches for targeting pre-CSCs in T-ALL by using therapies directed at oncogenic transcription factors themselves, downstream self-renewal pathways, and the supportive cell niche. Clin Cancer Res 16(23) 5618–23. ©2010 AACR.
Publisher: Wiley
Date: 15-05-2020
DOI: 10.1111/EJH.13431
Publisher: Springer Science and Business Media LLC
Date: 06-10-2014
DOI: 10.1038/LEU.2014.292
Abstract: Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute leukemias, in particular poor prognosis early T-cell precursor-like (ETP-) acute lymphoblastic leukemia (ALL). The primary effect of Lmo2 is to cause self-renewal of developing CD4(-)CD8(-) (double negative, DN) T cells in the thymus, leading to serially transplantable thymocytes that eventually give rise to leukemia. These self-renewing thymocytes are intrinsically radioresistant implying that they may be a source of leukemia relapse after therapy. The homeobox transcription factor, Hhex, is highly upregulated in Lmo2-transgenic thymocytes and can phenocopy Lmo2 in inducing thymocyte self-renewal, implying that Hhex may be a key component of the Lmo2-induced self-renewal program. To test this, we conditionally deleted Hhex in the thymi of Lmo2-transgenic mice. Surprisingly, this did not prevent accumulation of DN thymocytes, nor alter the rate of overt leukemia development. However, deletion of Hhex abolished the transplantation capacity of Lmo2-transgenic thymocytes and overcame their radioresistance. We found that Hhex regulates Kit expression in Lmo2-transgenic thymocytes and that abrogation of Kit signaling phenocopied loss of Hhex in abolishing the transplantation capacity and radioresistance of these cells. Thus, targeting the Kit signaling pathway may facilitate the eradication of leukemia-initiating cells in immature T-cell leukemias in which it is expressed.
Publisher: Informa UK Limited
Date: 15-06-2010
Publisher: Elsevier BV
Date: 03-2017
Publisher: Elsevier BV
Date: 2001
Publisher: Massachusetts Medical Society
Date: 10-06-2004
Publisher: American Society of Hematology
Date: 19-09-2013
DOI: 10.1182/BLOOD-2012-09-458570
Abstract: Lyl1 is required for Lmo2-induced T-cell leukemia in mice, whereas Scl is dispensable. LYL1 is required for growth of ETP-ALL cell lines.
Publisher: American Society for Clinical Investigation
Date: 12-1998
DOI: 10.1172/JCI3729
Publisher: Informa UK Limited
Date: 12-2003
Publisher: Oxford University Press (OUP)
Date: 19-06-2017
DOI: 10.1002/STEM.2648
Abstract: The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin−Sca+Kit+ cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16Ink4a and p19Arf. Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress.
Publisher: Springer New York
Date: 2018
DOI: 10.1007/978-1-4939-7568-6_15
Abstract: Chromatin Immunoprecipitation (ChIP) using antibodies specific for histone modifications is a powerful technique for assessing the epigenetic states of cell populations by either quantitative PCR (ChIP-PCR) or next generation sequencing analysis (ChIP-Seq). Here we describe the procedure for ChIP of histone marks in myeloid leukaemia cell lines and the subsequent purification of genomic DNA associated with repressive and activating histone modifications for further analysis. This procedure can be widely applied to a variety of histone marks to assess both activating and repressive modifications in the context of myeloid leukaemia.
Publisher: Rockefeller University Press
Date: 15-03-2023
DOI: 10.1084/JEM.20212383
Abstract: Cell competition has recently emerged as an important tumor suppressor mechanism in the thymus that inhibits autonomous thymic maintenance. Here, we show that the oncogenic transcription factor Lmo2 causes autonomous thymic maintenance in transgenic mice by inhibiting early T cell differentiation. This autonomous thymic maintenance results in the development of self-renewing preleukemic stem cells (pre-LSCs) and subsequent leukemogenesis, both of which are profoundly inhibited by restoration of thymic competition or expression of the antiapoptotic factor BCL2. Genomic analyses revealed the presence of Notch1 mutations in pre-LSCs before subsequent loss of tumor suppressors promotes the transition to overt leukemogenesis. These studies demonstrate a critical role for impaired cell competition in the development of pre-LSCs in a transgenic mouse model of T cell acute lymphoblastic leukemia (T-ALL), implying that this process plays a role in the ontogeny of human T-ALL.
Publisher: Elsevier BV
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 07-01-2015
DOI: 10.1038/NCOMMS6794
Abstract: Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2 -driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R . This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2 -driven mouse model.
Publisher: Springer Science and Business Media LLC
Date: 02-12-1999
Abstract: Several constitutively active mutant forms of the common beta subunit of the human IL-3, IL-5 and GM-CSF receptors (hbetac), which enable it to signal in the absence of ligand, have recently been described. Two of these, V449E and I374N, are amino acid substitutions in the transmembrane and extracellular regions of hbetac, respectively. A third, FIDelta, contains a 37 amino acid duplication in the extracellular domain. We have shown previously that when expressed in primary murine haemopoietic cells, the extracellular mutants confer factor-independence on cells of the neutrophil and monocyte lineages only, whereas V449E does so on all cell types of the myeloid and erythroid compartments. To study the in vivo effects and leukaemic potential of these mutants, we have expressed all three in mice by bone marrow reconstitution using retrovirally infected donor cells. Expression of the extracellular mutants leads to an early onset, chronic myeloproliferative disorder marked by elevations in the neutrophil, monocyte, erythrocyte and platelet lineages. In contrast, expression of V449E leads to an acute leukaemia-like syndrome of anaemia, thrombocytopaenia and blast cell expansion. These data support the possibility that activating mutations in hbetac are involved in haemopoietic disorders in man.
Publisher: Cold Spring Harbor Laboratory
Date: 2016
Abstract: Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we found that the hematopoietically expressed homeobox gene Hhex is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to expression of the Cdkn2a -encoded tumor suppressors p16 INK4a and p19 ARF , which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and directly interacts with the Polycomb-repressive complex 2 (PRC2) to enable H3K27me3-mediated epigenetic repression. Thus, Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.
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.
Publisher: American Society of Hematology
Date: 20-01-2022
Publisher: Springer Science and Business Media LLC
Date: 30-01-2019
DOI: 10.1038/S41375-018-0361-0
Abstract: T cell acute lymphoblastic leukaemia (T-ALL) cases include subfamilies that overexpress the TAL1/LMO, TLX1/3 and HOXA transcription factor oncogenes. While it has been shown that TAL1/LMO transcription factors induce self-renewal of thymocytes, whether this is true for other transcription factor oncogenes is unknown. To address this, we have studied NUP98-HOXD13-transgenic (NHD13-Tg) mice, which overexpress HOXA transcription factors throughout haematopoiesis and develop both myelodysplastic syndrome (MDS) progressing to acute myeloid leukaemia (AML) as well as T-ALL. We find that thymocytes from preleukaemic NHD13-Tg mice can serially transplant, demonstrating that they have self-renewal capacity. Transcriptome analysis shows that NHD13-Tg thymocytes exhibit a stem cell-like transcriptional programme closely resembling that induced by Lmo2, including Lmo2 itself and its critical cofactor Lyl1. To determine whether Lmo2/Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice. This showed that Lyl1 is essential for expression of the stem cell-like gene expression programme in thymocytes and self-renewal. Surprisingly however, NHD13 transgenic mice lacking Lyl1 showed accelerated T-ALL and absence of transformation to AML, associated with a loss of multipotent progenitors in the bone marrow. Thus multiple T cell oncogenes induce thymocyte self-renewal via Lmo2/Lyl1 however, NHD13 can also promote T-ALL via an alternative pathway.
Publisher: Springer Science and Business Media LLC
Date: 19-10-2020
DOI: 10.1038/S41590-020-0799-X
Abstract: A classical view of blood cell development is that multipotent hematopoietic stem and progenitor cells (HSPCs) become lineage-restricted at defined stages. Lin
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S1535-6108(03)00106-5
Abstract: The etiology of human tumors often involves chromosomal translocations. Models that emulate translocations are essential to understanding the determinants of frank malignancy, those dictating the restriction of translocations to specific lineages, and as a basis for development of rational therapeutic methods. We demonstrate that developmentally regulated Cre-loxP-mediated interchromosomal recombination between the Mll gene, whose human counterpart is involved in a spectrum of leukemias, and the Enl gene creates reciprocal chromosomal translocations that cause myeloid tumors. There is a rapid onset and high penetrance of leukemogenesis in these translocator mice, and high proportions of cells carrying chromosomal translocations can be found in bone marrow as early as 12 days after birth. This de novo strategy is a direct recapitulation of naturally occurring human cancer-associated translocations.
Publisher: American Society of Hematology
Date: 29-01-2015
DOI: 10.1182/BLOOD-2014-06-579813
Abstract: Hhex regulates development of erse lymphoid lineages. Hhex regulates cycling of lymphoid precursors.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2021
Location: Portugal
Location: Australia
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2016
End Date: 2019
Funder: Fundação para a Ciência e a Tecnologia
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