The Experts below are selected from a list of 1062 Experts worldwide ranked by ideXlab platform
David J Curtis - One of the best experts on this subject based on the ideXlab platform.
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The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/LYL1
Leukemia, 2019Co-Authors: Benjamin J. Shields, David J Curtis, Jacob T. Jackson, Christopher I. Slape, Adriana Pliego-zamora, Hansini Ranasinghe, Wei Shi, Matthew P MccormackAbstract: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.
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the nup98 hoxd13 fusion oncogene induces thymocyte self renewal via lmo2 LYL1
Leukemia, 2019Co-Authors: Benjamin J. Shields, David J Curtis, Jacob T. Jackson, Christopher I. Slape, Hansini Ranasinghe, Wei Shi, Adriana Pliegozamora, Matthew P MccormackAbstract: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.
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The NUP98-HOXD13 Fusion Oncogene Induces Thymocyte Self-Renewal Via Lmo2/LYL1
Blood, 2018Co-Authors: Benjamin J. Shields, David J Curtis, Jacob T. Jackson, Christopher I. Slape, Wei Shi, Matthew P MccormackAbstract:Abstract T-cell Acute Lymphoblastic Leukaemias (T-ALL) cases include subfamilies that overexpress the TAL1/LMO, TLX1/3 and HOXA transcription factor oncogenes. Whilst 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 leukemia (AML) as well as T-ALL. We find that thymocytes from preleukemic 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 program 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 program 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. Disclosures Curtis: MERCK: Membership on an entity's Board of Directors or advisory committees; CRC Cancer Therapeutics: Patents & Royalties, Research Funding.
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A novel role for LYL1 in primitive erythropoiesis.
Development (Cambridge England), 2018Co-Authors: Sung Kai Chiu, Cedric S Tremblay, John E. Pimanda, Jesslyn Saw, Yizhou Huang, Stefan Eugen Sonderegger, Nicholas C. Wong, David R. Powell, Dominic Beck, David J CurtisAbstract:Stem cell leukemia (Scl or Tal1) and lymphoblastic leukemia 1 (LYL1) encode highly related members of the basic helix-loop-helix family of transcription factors that are co-expressed in the erythroid lineage. Previous studies have suggested that Scl is essential for primitive erythropoiesis. However, analysis of single-cell RNA-seq data of early embryos showed that primitive erythroid cells express both Scl and LYL1 Therefore, to determine whether LYL1 can function in primitive erythropoiesis, we crossed conditional Scl knockout mice with mice expressing a Cre recombinase under the control of the Epo receptor, active in erythroid progenitors. Embryos with 20% expression of Scl from E9.5 survived to adulthood. However, mice with reduced expression of Scl and absence of LYL1 (double knockout; DKO) died at E10.5 because of progressive loss of erythropoiesis. Gene expression profiling of DKO yolk sacs revealed loss of Gata1 and many of the known target genes of the SCL-GATA1 complex. ChIP-seq analyses in a human erythroleukemia cell line showed that LYL1 exclusively bound a small subset of SCL targets including GATA1. Together, these data show for the first time that LYL1 can maintain primitive erythropoiesis.
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Either Scl or LYL1 Is Required to Maintain Primitive Erythropoiesis
Blood, 2016Co-Authors: Sung Kai Chiu, Cedric S Tremblay, Jesslyn Saw, David J CurtisAbstract:Abstract SCL (TAL1) and LYL1 are the predominant bHLH transcription factors expressed in erythropoiesis. Using a conditional allele of Scl, we have previously demonstrated redundancy of Scl in adult erythropoiesis. Similarly, adult erythropoiesis is maintained in LYL1-deficient mice. To determine if these factors can compensate for each other, we deleted Scl with Cre recombinase under the control of the Epo receptor, which is active in late erythroid progenitors from embryonic day 8.5. Embryos lacking Scl in erythroid progenitors (EpoR-Cre SclD/D) were born at the expected Mendelian frequency with only a mild anemia in adult mice, indicating Scl was not required for primitive or definitive erythropoiesis. In contrast EpoR-Cre SclD/D mice lacking LYL1 died at e11.5 due to erythropoietic collapse. Gene expression profiling of yolk sacs prior to the loss of erythrocytes (E9.5) revealed reduced Gata1, Fog1, Klf1 and the primitive b-globins. In contrast, expression of Gata2 and Runx1 were increased despite absence of Scl and LYL1. Development of embryonic stem cells from these mice will determine if Gata1 is key downstream target of the Scl/LYL1 complex for primitive erythropoiesis. Disclosures No relevant conflicts of interest to declare.
Mark D Minden - One of the best experts on this subject based on the ideXlab platform.
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© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity
2016Co-Authors: Atlas Genet, Yue-sheng Meng, Cytogenet Oncol Haematol, Mark D MindenAbstract:Location of the LYL1 gene, identified by Non-random chromosomal translocation t(7;19)(q35;p13) associated with T-cell acute lymphoblastic leukemia (T-ALL), was mapped to the short arm of chromosome 19 (19p13) by in situ hybridization. Transcription Expression levels of LYL1 are comparatively higher in normal bone marrow, spleen, lung, thymus and spinal cord tissues. Ectopic transcription is observed in T-lymphoblastic and myeloblastic leukemic cells
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suspected leukemia oncoproteins creb1 and LYL1 regulate op18 stmn1 expression
Biochimica et Biophysica Acta, 2012Co-Authors: Serban Sanmarina, Youqi Han, Jian Liu, Mark D MindenAbstract:Stathmin (STMN1) is a microtubule destabilizing protein with a key role in cell cycle progression and cell migration that is up-regulated in several cancers and may contribute to the malignant phenotype. However, the factors that regulate its expression are not well understood. Loss as well as gain-of-function p53 mutations up-regulate STMN1 and in acute myelogenous leukemia where p53 is predominantly wild-type, STMN1 is also over-expressed. Here we show regulatory control of STMN1 expression by the leucine zipper transcription factor (TF) CREB1 and the basic helix-loop-helix TF LYL1. By ChIP-chip experiments we demonstrate in vivo the presence of LYL1 and CREB1 in close proximity on the STMN1 promoter and using promoter assays we reveal co-regulation of STMN1 by CREB1 and LYL1. By contrast, TAL1, another suspected oncoprotein in leukemia and close relative of LYL1, exerts no regulatory effect on the STMN1 promoter. NLI, LMO2 and GATA2 are previously described co-activators of Tal1/LYL1-E47 transcriptional complexes and potentiate LYL1 activation of the STMN1 promoter while having no effect on TAL1 transactivation. Promoter mutations that abrogate CREB1 proximal binding or mutations of the DNA-binding domain of CREB1 abolish LYL1 transcriptional activation. These results show that CRE and Ebox sites function as coordinated units and support previous evidence of joint CREB1-and LYL1 transcription events activating an aberrant subset of promoters in leukemia. CREB1 or LYL1 shRNA knock-down down-regulate STMN1 expression. Because down-regulation of STMN1 has been shown to have anti-proliferative effects, while CREB1 and LYL1 are suspected oncoproteins, interference with CREB1-LYL1 interactions may complement standard chemotherapy and yield additional beneficial effects.
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Suspected leukemia oncoproteins CREB1 and LYL1 regulate Op18/STMN1 expression.
Biochimica et biophysica acta, 2012Co-Authors: Serban San-marina, Youqi Han, Jian Liu, Mark D MindenAbstract:Stathmin (STMN1) is a microtubule destabilizing protein with a key role in cell cycle progression and cell migration that is up-regulated in several cancers and may contribute to the malignant phenotype. However, the factors that regulate its expression are not well understood. Loss as well as gain-of-function p53 mutations up-regulate STMN1 and in acute myelogenous leukemia where p53 is predominantly wild-type, STMN1 is also over-expressed. Here we show regulatory control of STMN1 expression by the leucine zipper transcription factor (TF) CREB1 and the basic helix-loop-helix TF LYL1. By ChIP-chip experiments we demonstrate in vivo the presence of LYL1 and CREB1 in close proximity on the STMN1 promoter and using promoter assays we reveal co-regulation of STMN1 by CREB1 and LYL1. By contrast, TAL1, another suspected oncoprotein in leukemia and close relative of LYL1, exerts no regulatory effect on the STMN1 promoter. NLI, LMO2 and GATA2 are previously described co-activators of Tal1/LYL1-E47 transcriptional complexes and potentiate LYL1 activation of the STMN1 promoter while having no effect on TAL1 transactivation. Promoter mutations that abrogate CREB1 proximal binding or mutations of the DNA-binding domain of CREB1 abolish LYL1 transcriptional activation. These results show that CRE and Ebox sites function as coordinated units and support previous evidence of joint CREB1-and LYL1 transcription events activating an aberrant subset of promoters in leukemia. CREB1 or LYL1 shRNA knock-down down-regulate STMN1 expression. Because down-regulation of STMN1 has been shown to have anti-proliferative effects, while CREB1 and LYL1 are suspected oncoproteins, interference with CREB1-LYL1 interactions may complement standard chemotherapy and yield additional beneficial effects.
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LYL1 interacts with CREB1 and alters expression of CREB1 target genes.
Biochimica et biophysica acta, 2007Co-Authors: Serban San-marina, Youqi Han, Fernando Jose Suarez Saiz, Michael Trus, Mark D MindenAbstract:The basic helix-loop-helix (bHLH) transcription factor family contains key regulators of cellular proliferation and differentiation as well as the suspected oncoproteins Tal1 and LYL1. Tal1 and LYL1 are aberrantly over-expressed in leukemia as a result of chromosomal translocations, or other genetic or epigenetic events. Protein-protein and protein-DNA interactions described so far are mediated by their highly homologous bHLH domains, while little is known about the function of other protein domains. Hetero-dimers of Tal1 and LYL1 with E2A or HEB, decrease the rate of E2A or HEB homo-dimer formation and are poor activators of transcription. In vitro, these hetero-dimers also recognize different binding sites from homo-dimer complexes, which may also lead to inappropriate activation or repression of promoters in vivo. Both mechanisms are thought to contribute to the oncogenic potential of Tal1 and LYL1. Despite their bHLH structural similarity, accumulating evidence suggests that Tal1 and LYL1 target different genes. This raises the possibility that domains flanking the bHLH region, which are distinct in the two proteins, may participate in target recognition. Here we report that CREB1, a widely-expressed transcription factor and a suspected oncogene in acute myelogenous leukemia (AML) was identified as a binding partner for LYL1 but not for Tal1. The interaction between LYL1 and CREB1 involves the N terminal domain of LYL1 and the Q2 and KID domains of CREB1. The histone acetyl-transferases p300 and CBP are recruited to these complexes in the absence of CREB1 Ser 133 phosphorylation. In the Id1 promoter, LYL1 complexes direct transcriptional activation. We also found that in addition to Id1, over-expressed LYL1 can activate other CREB1 target promoters such as Id3, cyclin D3, Brca1, Btg2 and Egr1. Moreover, approximately 50% of all gene promoters identified by ChIP-chip experiments were jointly occupied by CREB1 and LYL1, further strengthening the association of LYL1 with Cre binding sites. Given the newly recognized importance of CREB1 in AML, the ability of LYL1 to modulate promoter responses to CREB1 suggests that it plays a role in the malignant phenotype by occupying different promoters than Tal1.
Cedric S Tremblay - One of the best experts on this subject based on the ideXlab platform.
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A novel role for LYL1 in primitive erythropoiesis.
Development (Cambridge England), 2018Co-Authors: Sung Kai Chiu, Cedric S Tremblay, John E. Pimanda, Jesslyn Saw, Yizhou Huang, Stefan Eugen Sonderegger, Nicholas C. Wong, David R. Powell, Dominic Beck, David J CurtisAbstract:Stem cell leukemia (Scl or Tal1) and lymphoblastic leukemia 1 (LYL1) encode highly related members of the basic helix-loop-helix family of transcription factors that are co-expressed in the erythroid lineage. Previous studies have suggested that Scl is essential for primitive erythropoiesis. However, analysis of single-cell RNA-seq data of early embryos showed that primitive erythroid cells express both Scl and LYL1 Therefore, to determine whether LYL1 can function in primitive erythropoiesis, we crossed conditional Scl knockout mice with mice expressing a Cre recombinase under the control of the Epo receptor, active in erythroid progenitors. Embryos with 20% expression of Scl from E9.5 survived to adulthood. However, mice with reduced expression of Scl and absence of LYL1 (double knockout; DKO) died at E10.5 because of progressive loss of erythropoiesis. Gene expression profiling of DKO yolk sacs revealed loss of Gata1 and many of the known target genes of the SCL-GATA1 complex. ChIP-seq analyses in a human erythroleukemia cell line showed that LYL1 exclusively bound a small subset of SCL targets including GATA1. Together, these data show for the first time that LYL1 can maintain primitive erythropoiesis.
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Either Scl or LYL1 Is Required to Maintain Primitive Erythropoiesis
Blood, 2016Co-Authors: Sung Kai Chiu, Cedric S Tremblay, Jesslyn Saw, David J CurtisAbstract:Abstract SCL (TAL1) and LYL1 are the predominant bHLH transcription factors expressed in erythropoiesis. Using a conditional allele of Scl, we have previously demonstrated redundancy of Scl in adult erythropoiesis. Similarly, adult erythropoiesis is maintained in LYL1-deficient mice. To determine if these factors can compensate for each other, we deleted Scl with Cre recombinase under the control of the Epo receptor, which is active in late erythroid progenitors from embryonic day 8.5. Embryos lacking Scl in erythroid progenitors (EpoR-Cre SclD/D) were born at the expected Mendelian frequency with only a mild anemia in adult mice, indicating Scl was not required for primitive or definitive erythropoiesis. In contrast EpoR-Cre SclD/D mice lacking LYL1 died at e11.5 due to erythropoietic collapse. Gene expression profiling of yolk sacs prior to the loss of erythrocytes (E9.5) revealed reduced Gata1, Fog1, Klf1 and the primitive b-globins. In contrast, expression of Gata2 and Runx1 were increased despite absence of Scl and LYL1. Development of embryonic stem cells from these mice will determine if Gata1 is key downstream target of the Scl/LYL1 complex for primitive erythropoiesis. Disclosures No relevant conflicts of interest to declare.
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SCL, LMO1 and Notch1 Reprogram Thymocytes into Self- Renewing Cells
2016Co-Authors: Bastien Gerby, Cedric S Tremblay, Mathieu Tremblay, Shanti Rojas-sutterlin, Guy Sauvageau, Diogo F.t. Veiga, Trang HoangAbstract:The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem cells are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model to define the critical initiating events in this disease. First, thymocytes that are reprogrammed by the SCL and LMO1 oncogenic transcription factors into self-renewing pre-leukemic stem cells (pre-LSCs) remain non-malignant, as evidenced by their capacities to generate functional T cells. Second, we provide strong genetic evidence that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1. Moreover, LYL1 can substitute for SCL to reprogram thymocytes in concert with LMO1. In contrast, inhibition of E2A was not sufficient to substitute for SCL, indicating that thymocyte reprogramming requires transcription activation by SCL-LMO1. Third, only a specific subset of normal thymic cells, known as DN3 thymocytes, is susceptible to reprogramming. This is because physiological NOTCH1 signals are highest in DN3 cells compared to other thymocyte subsets. Consistent with this, overexpression of a ligand-independent hyperactive NOTCH1 allele in all immature thymocytes is sufficient to sensitize them to SCL-LMO1, thereby increasing the pool of self-renewing cells. Surprisingly, hyperactive NOTCH1 cannot reprogram thymocytes on its own, despite the fact that NOTCH1 is activated by gain of function mutations in more than 55 % of T-ALL cases. Rather, elevatin
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Scl and LYL1 Are Redundant in Erythropoiesis
Blood, 2015Co-Authors: Sung Kai Chiu, Cedric S Tremblay, Jesslyn Saw, David J CurtisAbstract:Stem cell leukaemia (Scl) and Lymphoblastic lymphoma derived sequence 1 (LYL1) are the only hematopoiesis-specific basic Helix-loop-helix (bHLH) transcription factors. During development, LYL1 is unable to compensate for Scl; with death of Scl-null embryos at e9.5 due complete absence of primitive hematopoiesis and defective vascular development. In contrast, LYL1 can compensate for Scl in adult hematopoietic stem cells. To further explore the role of these two bHLH factors during hematopoietic development, we deleted Scl with Cre recombinase under the control of the Epo receptor, which is active in late erythroid progenitors. Surprisingly, embryos lacking Scl in erythroid progenitors (EpoR-Cre SclD/D) were born at the expected Mendelian frequency with only a mild anemia in adult mice. In contrast EpoR-Cre SclD/D mice lacking LYL1 died at e11.5-12.5 due to erythropoietic collapse (see figure 1). These experiments provide the first evidence for an important role of LYL1 in erythroid development and suggest that death of Scl-null embryos is due to defects in endothelial development rather than lack of primitive erythropoiesis. Disclosures No relevant conflicts of interest to declare.
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SCL, LMO1 and Notch1 Reprogram Thymocytes into Self-Renewing Cells
PLoS genetics, 2014Co-Authors: Bastien Gerby, Sabine Herblot, Cedric S Tremblay, Mathieu Tremblay, Shanti Rojas-sutterlin, Josée Hébert, Guy Sauvageau, Sébastien Lemieux, Eric Lécuyer, Diogo F.t. VeigaAbstract:The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem cells are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model to define the critical initiating events in this disease. First, thymocytes that are reprogrammed by the SCL and LMO1 oncogenic transcription factors into self-renewing pre-leukemic stem cells (pre-LSCs) remain non-malignant, as evidenced by their capacities to generate functional T cells. Second, we provide strong genetic evidence that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1. Moreover, LYL1 can substitute for SCL to reprogram thymocytes in concert with LMO1. In contrast, inhibition of E2A was not sufficient to substitute for SCL, indicating that thymocyte reprogramming requires transcription activation by SCL-LMO1. Third, only a specific subset of normal thymic cells, known as DN3 thymocytes, is susceptible to reprogramming. This is because physiological NOTCH1 signals are highest in DN3 cells compared to other thymocyte subsets. Consistent with this, overexpression of a ligand-independent hyperactive NOTCH1 allele in all immature thymocytes is sufficient to sensitize them to SCL-LMO1, thereby increasing the pool of self-renewing cells. Surprisingly, hyperactive NOTCH1 cannot reprogram thymocytes on its own, despite the fact that NOTCH1 is activated by gain of function mutations in more than 55% of T-ALL cases. Rather, elevating NOTCH1 triggers a parallel pathway involving Hes1 and Myc that dramatically enhances the activity of SCL-LMO1 We conclude that the acquisition of self-renewal and the genesis of pre-LSCs from thymocytes with a finite lifespan represent a critical first event in T-ALL. Finally, LYL1 and LMO1 or LMO2 are co-expressed in most human T-ALL samples, except the cortical T subtype. We therefore anticipate that the self-renewal network described here may be relevant to a majority of human T-ALL.
Valérie Pinet - One of the best experts on this subject based on the ideXlab platform.
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in LYL1 mice adipose stem cell vascular niche impairment leads to premature development of fat tissues
Stem Cells, 2021Co-Authors: Abid Hussain, Nelly Pirot, Virginie Deleuze, Danièle Mathieu, Leila El Kebriti, Hulya Turali, Yaël Glasson, Valérie PinetAbstract:LYL1 encodes a hematopoietic- and endothelial-specific bHLH transcription factor. LYL1-deficient mice are viable, but they display mild hematopoietic and vascular defects. Specifically, LYL1 is required for the maturation and stabilization of blood vessel endothelial adherens junctions. Here, we report that young adult LYL1-/- mice exhibit transient overweight associated with general expansion of adipose tissue, without signs of metabolic disorder and unrelated to food intake. The increased fat tissue development in LYL1-/- mice resulted from earlier differentiation of adipose stem cells (ASCs) into adipocytes through noncell autonomous mechanisms. Specifically, we found that in LYL1-/- mice, the adipose tissue vascular structures are immature, as indicated by their high permeability, reduced coverage by pericytes, lower recruitment of VE-cadherin and ZO1 at cell junctions, and more prone to angiogenesis. Together, our data show that in LYL1-/- mice, the impaired vascular compartment of the adipose niche promotes ASC differentiation, leading to early adipocyte expansion and premature ASC depletion. Our study highlights the major structural role of the adipose tissue vascular niche in coordinating stem cell self-renewal and differentiation into adipocytes.
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Angiopoietin-2 is a direct transcriptional target of TAL1, LYL1 and LMO2 in endothelial cells.
PLoS ONE, 2020Co-Authors: Virginie Deleuze, Rawan El-hajj, Christiane Dohet, Philippe Couttet, Valérie Pinet, Elias Chalhoub, Danièle MathieuAbstract:The two related basic helix-loop-helix, TAL1 and LYL1, and their cofactor LIM-only-2 protein (LMO2) are present in blood and endothelial cells. While their crucial role in early hematopoiesis is well established, their function in endothelial cells and especially in angiogenesis is less understood. Here, we identified ANGIOPOIETIN-2 (ANG-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of TAL1, LYL1 and LMO2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ANG-2 mRNA and protein down-regulation. Transient transfections showed that the full activity of the ANG-2 promoter required the integrity of a highly conserved Ebox-GATA composite element. Accordingly, chromatin immunoprecipitation assays demonstrated that TAL1, LYL1, LMO2 and GATA2 occupied this region of ANG-2 promoter in human endothelial cells. Furthermore, we showed that LMO2 played a central role in assembling TAL1-E47, LYL1-LYL1 or/and LYL1-TAL1 dimers with GATA2. The resulting complexes were able to activate endogenous ANG-2 expression in endothelial cells as well as in non-endothelial cells. Finally, we showed that ANG-2 gene activation during angiogenesis concurred with the up-regulation of TAL1 and LMO2. Altogether, we identified ANG-2 as a bona fide target gene of LMO2-complexes with TAL1 and/or LYL1, highlighting a new function of the three hematopoietic factors in the endothelial lineage.
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In LYL1-/- mice, adipose stem cell vascular niche impairment leads to premature development of fat tissues.
Stem cells (Dayton Ohio), 2020Co-Authors: Abid Hussain, Nelly Pirot, Virginie Deleuze, Danièle Mathieu, Leila El Kebriti, Hulya Turali, Yaël Glasson, Valérie PinetAbstract:LYL1 encodes a hematopoietic- and endothelial-specific bHLH transcription factor. LYL1-deficient mice are viable, but they display mild hematopoietic and vascular defects. Specifically, LYL1 is required for the maturation and stabilization of blood vessel endothelial adherens junctions. Here, we report that young adult LYL1-/- mice exhibit transient overweight associated with general expansion of adipose tissue, without signs of metabolic disorder and unrelated to food intake. The increased fat tissue development in LYL1-/- mice resulted from earlier differentiation of adipose stem cells (ASCs) into adipocytes through noncell autonomous mechanisms. Specifically, we found that in LYL1-/- mice, the adipose tissue vascular structures are immature, as indicated by their high permeability, reduced coverage by pericytes, lower recruitment of VE-cadherin and ZO1 at cell junctions, and more prone to angiogenesis. Together, our data show that in LYL1-/- mice, the impaired vascular compartment of the adipose niche promotes ASC differentiation, leading to early adipocyte expansion and premature ASC depletion. Our study highlights the major structural role of the adipose tissue vascular niche in coordinating stem cell self-renewal and differentiation into adipocytes.
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In LYL1-/- mice, adipose stem cell vascular niche impairment leads to premature development of fat tissues
2020Co-Authors: Abid Hussain, Nelly Pirot, Virginie Deleuze, Danièle Mathieu, Leila El Kebriti, Yaël Glasson, Valérie PinetAbstract:ABSTRACT Lymphoblastic leukemia-derived sequence 1 (LYL1) encodes a hematopoietic- and endothelial-specific transcriptional factor. LYL1-deficient mice are viable, but they display mild hematopoietic and vascular defects. Here, we report that young LYL1-/- mice exhibit transient obesity associated with general expansion of adipose tissues and unrelated to food intake. The increased fat tissue development in LYL1-/- mice resulted from an earlier adipocyte differentiation of adipose stem cells (ASCs) through non-cell autonomous mechanisms. Specifically, we found that in LYL1-/- mice, the vascular structures of adipose tissues are unstable, more prone to angiogenesis and, consequently, cannot maintain adipose progenitors in the niche vessel wall. Together, our data show that in LYL1-/- mice, the impaired vascular compartment of the adipose niche promotes uncontrolled ASC activation and differentiation, leading to early adipocyte expansion and premature depletion of ASCs. Our study highlights the major structural role of the adipose tissue vascular niche in coordinating stem cell self-renewal and differentiation into adipocytes.
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in LYL1 mice adipose stem cell vascular niche impairment leads to premature development of fat tissues
bioRxiv, 2020Co-Authors: Abid Hussain, Nelly Pirot, Virginie Deleuze, Danièle Mathieu, Leila El Kebriti, Yaël Glasson, Valérie PinetAbstract:ABSTRACT Lymphoblastic leukemia-derived sequence 1 (LYL1) encodes a hematopoietic- and endothelial-specific transcriptional factor. LYL1-deficient mice are viable, but they display mild hematopoietic and vascular defects. Here, we report that young LYL1-/- mice exhibit transient obesity associated with general expansion of adipose tissues and unrelated to food intake. The increased fat tissue development in LYL1-/- mice resulted from an earlier adipocyte differentiation of adipose stem cells (ASCs) through non-cell autonomous mechanisms. Specifically, we found that in LYL1-/- mice, the vascular structures of adipose tissues are unstable, more prone to angiogenesis and, consequently, cannot maintain adipose progenitors in the niche vessel wall. Together, our data show that in LYL1-/- mice, the impaired vascular compartment of the adipose niche promotes uncontrolled ASC activation and differentiation, leading to early adipocyte expansion and premature depletion of ASCs. Our study highlights the major structural role of the adipose tissue vascular niche in coordinating stem cell self-renewal and differentiation into adipocytes.
Youqi Han - One of the best experts on this subject based on the ideXlab platform.
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suspected leukemia oncoproteins creb1 and LYL1 regulate op18 stmn1 expression
Biochimica et Biophysica Acta, 2012Co-Authors: Serban Sanmarina, Youqi Han, Jian Liu, Mark D MindenAbstract:Stathmin (STMN1) is a microtubule destabilizing protein with a key role in cell cycle progression and cell migration that is up-regulated in several cancers and may contribute to the malignant phenotype. However, the factors that regulate its expression are not well understood. Loss as well as gain-of-function p53 mutations up-regulate STMN1 and in acute myelogenous leukemia where p53 is predominantly wild-type, STMN1 is also over-expressed. Here we show regulatory control of STMN1 expression by the leucine zipper transcription factor (TF) CREB1 and the basic helix-loop-helix TF LYL1. By ChIP-chip experiments we demonstrate in vivo the presence of LYL1 and CREB1 in close proximity on the STMN1 promoter and using promoter assays we reveal co-regulation of STMN1 by CREB1 and LYL1. By contrast, TAL1, another suspected oncoprotein in leukemia and close relative of LYL1, exerts no regulatory effect on the STMN1 promoter. NLI, LMO2 and GATA2 are previously described co-activators of Tal1/LYL1-E47 transcriptional complexes and potentiate LYL1 activation of the STMN1 promoter while having no effect on TAL1 transactivation. Promoter mutations that abrogate CREB1 proximal binding or mutations of the DNA-binding domain of CREB1 abolish LYL1 transcriptional activation. These results show that CRE and Ebox sites function as coordinated units and support previous evidence of joint CREB1-and LYL1 transcription events activating an aberrant subset of promoters in leukemia. CREB1 or LYL1 shRNA knock-down down-regulate STMN1 expression. Because down-regulation of STMN1 has been shown to have anti-proliferative effects, while CREB1 and LYL1 are suspected oncoproteins, interference with CREB1-LYL1 interactions may complement standard chemotherapy and yield additional beneficial effects.
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Suspected leukemia oncoproteins CREB1 and LYL1 regulate Op18/STMN1 expression.
Biochimica et biophysica acta, 2012Co-Authors: Serban San-marina, Youqi Han, Jian Liu, Mark D MindenAbstract:Stathmin (STMN1) is a microtubule destabilizing protein with a key role in cell cycle progression and cell migration that is up-regulated in several cancers and may contribute to the malignant phenotype. However, the factors that regulate its expression are not well understood. Loss as well as gain-of-function p53 mutations up-regulate STMN1 and in acute myelogenous leukemia where p53 is predominantly wild-type, STMN1 is also over-expressed. Here we show regulatory control of STMN1 expression by the leucine zipper transcription factor (TF) CREB1 and the basic helix-loop-helix TF LYL1. By ChIP-chip experiments we demonstrate in vivo the presence of LYL1 and CREB1 in close proximity on the STMN1 promoter and using promoter assays we reveal co-regulation of STMN1 by CREB1 and LYL1. By contrast, TAL1, another suspected oncoprotein in leukemia and close relative of LYL1, exerts no regulatory effect on the STMN1 promoter. NLI, LMO2 and GATA2 are previously described co-activators of Tal1/LYL1-E47 transcriptional complexes and potentiate LYL1 activation of the STMN1 promoter while having no effect on TAL1 transactivation. Promoter mutations that abrogate CREB1 proximal binding or mutations of the DNA-binding domain of CREB1 abolish LYL1 transcriptional activation. These results show that CRE and Ebox sites function as coordinated units and support previous evidence of joint CREB1-and LYL1 transcription events activating an aberrant subset of promoters in leukemia. CREB1 or LYL1 shRNA knock-down down-regulate STMN1 expression. Because down-regulation of STMN1 has been shown to have anti-proliferative effects, while CREB1 and LYL1 are suspected oncoproteins, interference with CREB1-LYL1 interactions may complement standard chemotherapy and yield additional beneficial effects.
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LYL1 interacts with CREB1 and alters expression of CREB1 target genes.
Biochimica et biophysica acta, 2007Co-Authors: Serban San-marina, Youqi Han, Fernando Jose Suarez Saiz, Michael Trus, Mark D MindenAbstract:The basic helix-loop-helix (bHLH) transcription factor family contains key regulators of cellular proliferation and differentiation as well as the suspected oncoproteins Tal1 and LYL1. Tal1 and LYL1 are aberrantly over-expressed in leukemia as a result of chromosomal translocations, or other genetic or epigenetic events. Protein-protein and protein-DNA interactions described so far are mediated by their highly homologous bHLH domains, while little is known about the function of other protein domains. Hetero-dimers of Tal1 and LYL1 with E2A or HEB, decrease the rate of E2A or HEB homo-dimer formation and are poor activators of transcription. In vitro, these hetero-dimers also recognize different binding sites from homo-dimer complexes, which may also lead to inappropriate activation or repression of promoters in vivo. Both mechanisms are thought to contribute to the oncogenic potential of Tal1 and LYL1. Despite their bHLH structural similarity, accumulating evidence suggests that Tal1 and LYL1 target different genes. This raises the possibility that domains flanking the bHLH region, which are distinct in the two proteins, may participate in target recognition. Here we report that CREB1, a widely-expressed transcription factor and a suspected oncogene in acute myelogenous leukemia (AML) was identified as a binding partner for LYL1 but not for Tal1. The interaction between LYL1 and CREB1 involves the N terminal domain of LYL1 and the Q2 and KID domains of CREB1. The histone acetyl-transferases p300 and CBP are recruited to these complexes in the absence of CREB1 Ser 133 phosphorylation. In the Id1 promoter, LYL1 complexes direct transcriptional activation. We also found that in addition to Id1, over-expressed LYL1 can activate other CREB1 target promoters such as Id3, cyclin D3, Brca1, Btg2 and Egr1. Moreover, approximately 50% of all gene promoters identified by ChIP-chip experiments were jointly occupied by CREB1 and LYL1, further strengthening the association of LYL1 with Cre binding sites. Given the newly recognized importance of CREB1 in AML, the ability of LYL1 to modulate promoter responses to CREB1 suggests that it plays a role in the malignant phenotype by occupying different promoters than Tal1.
