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Maarten Van Lohuizen - One of the best experts on this subject based on the ideXlab platform.

  • BMI1 Is Required for Hedgehog Pathway-Driven
    2020
    Co-Authors: Lowell Evan Michael, Maarten Van Lohuizen, Bart A. Westerman, Alexandre N. Ermilov, Aiqin Wang, Jennifer Ferris, Marleen Blom, David W. Ellison, Andrzej A. Dlugosz
    Abstract:

    Inappropriate Hedgehog (Hh) signaling underlies development of a subset of medulloblastomas, and tumors with elevated HH signaling activity express the stem cell self-renewal gene BMI1. To test whether BMI1 is required for Hh-driven medulloblastoma development, we varied BMI1 gene dosage in transgenic mice expressing an oncogenic Hh effector, SmoA1, driven by a glial fibrillary acidic protein (GFAP) promoter. Whereas 100% of SmoA1; BMI1 +/+ or SmoA1;BMI1 +/− mice examined between postnatal (P) days 14 and 26 had typical medulloblastomas (N = 29), tumors were not detected in any of the SmoA1;BMI1 −/− animals examined (N = 6). Instead, small ectopic collections of cells were present in the region of greatest tumor load in SmoA1 animals, suggesting that medulloblastomas were initiated but failed to undergo expansion into frank tumors. Cells within these BMI1 −/− lesions expressed SmoA1 but were largely nonproliferative, in contrast to cells in BMI1 +/+ tumors (6.2% vs 81.9% PCNA-positive, respectively). Ectopic cells were negative for the progenitor marker nestin, strongly GFAP–positive, and highly apoptotic, relative to BMI1 +/+ tumor cells (29.6% vs 6.3% TUNEL-positive). The alterations in proliferation and apoptosis in SmoA1;BMI1 −/− ectopic cells are associated with reduced levels of Cyclin D1 and elevated expression of cyclin-dependent kinase inhibitor p19 Arf , two inversely regulated downstream targets of BMI1. These data provide the first demonstration that BMI1 is required for spontaneous de novo development of a solid tumor arising in the brain, suggest a crucial role for BMI1-dependent, nestin-expressing progenitor cells in medulloblastoma expansion, and implicate BMI1 as a key factor required for Hh pathway-driven tumorigenesis.

  • BMI1 loss delays photoreceptor degeneration in Rd1 mice. BMI1 loss and neuroprotection in Rd1 mice
    Advances in Experimental Medicine and Biology, 2020
    Co-Authors: D. Zencak, Ellen Tanger, Maarten Van Lohuizen, M Tekaya, Francis L Munier, Daniel F Schorderet, Sylvain V. Crippa, Yvan Arsenijevic
    Abstract:

    Retinitis pigmentosa (RP) is a heterogeneous group of genetic disorders leading to blindness, which remain untreatable at present. Rd1 mice represent a recognized model of RP, and so far only GDNF treatment provided a slight delay in the retinal degeneration in these mice. BMI1, a transcriptional repressor, has recently been shown to be essential for neural stem cell (NSC) renewal in the brain, with an increased appearance of glial cells in vivo in BMI1 knockout (BMI1 -/-) mice. One of the roles of glial cells is to sustain neuronal function and survival. In the view of a role of the retinal Muller glia as a source of neural protection in the retina, the increased astrocytic population in the BMI1 -/- brain led us to investigate the effect of BMI1 loss in Rd1 mice. We observed an increase of Muller glial cells in Rd1-BMI1 -/- retinas compared to Rd1. Moreover, Rd1-BMI1 -/- mice showed 7–8 rows of photoreceptors at 30 days of age (P30), while in Rd1 littermates there was a complete disruption of the outer nuclear layer (ONL). Preliminary ERG results showed a responsiveness of Rd1-BMI1 -/- mice in scotopic vision at P35. In conclusion, BMI1 loss prevented, or rescued, photoreceptors from degeneration to an unanticipated extent in Rd1 mice.

  • Dual role of BMI1 loss in the preservation of photoreceptor layers in the Rd1 mouse
    Investigative Ophthalmology & Visual Science, 2012
    Co-Authors: Karine Schouwey, Maarten Van Lohuizen, D. Zencak, Yvan Arsenijevic
    Abstract:

    Purpose: In the Rd1 and Rd10 mouse models of retinitis pigmentosa, a mutation in the Pde6s gene leads to the rapid loss of photoreceptors. As in several neurodegenerative diseases, Rd1 and Rd10 photoreceptors re-express cell cycle proteins prior to death. BMI1 regulates cell cycle progression through inhibition of CDK inhibitors, and its deletion efficiently rescues the Rd1 retinal degeneration. The present study evaluates the effects of BMI1 loss in photoreceptors and Muller glia, since in lower vertebrates, these cells respond to retinal injury through dedifferentiation and regeneration of retinal cells. Methods: Cell death and Muller cell activation were analyzed by immunostaining of wild-type, Rd1 and Rd1;BMI1-/- eye sections during retinal degeneration, between P10 and P20. Lineage tracing experiments use the GFAP-Cre mouse (JAX) to target Muller cells. Results: In Rd1 retinal explants, inhibition of CDKs reduces the amount of dying cells. In vivo, BMI1 deletion reduces CDK4 expression and cell death in the P15 Rd1;BMI1-/- retina, although cGMP accumulation and TUNEL staining are detected at the onset of retinal degeneration (P12). This suggests that another process acts in parallel to overcome the initial loss of Rd1;BMI1-/- photoreceptors. We demonstrate here that BMI1 loss in the Rd1 retina enhances the activation of Muller glia by downregulation of p27Kip1, that these cells migrate toward the ONL, and that some cells express the retinal progenitor marker Pax6 at the inner part of the ONL. These events are also observed, but to a lesser extent, in Rd1 and Rd10 retinas. At P12, EdU incorporation shows proliferating cells with atypical elongated nuclei at the inner border of the Rd1;BMI1-/- ONL. Lineage tracing targeting Muller cells is in process and will determine the implication of this cell population in the maintenance of the Rd1;BMI1-/- ONL thickness and whether downregulation of BMI1 in Rd10 Muller cells equally stimulates their activation. Conclusions: Our results show a dual role of BMI1 deletion in the rescue of photoreceptors in the Rd1;BMI1-/- retina. Indeed, the loss of BMI1 reduces Rd1 retinal degeneration, and as well, enhances the Muller glia activation. In addition, the emergence of cells expressing a retinal progenitor marker in the ONL suggests BMI1 as a blockade to the regeneration of retinal cells in mammals.

  • functional crosstalk between BMI1 and mll hoxa9 axis in establishment of normal hematopoietic and leukemic stem cells
    Cell Stem Cell, 2011
    Co-Authors: Lanlan Smith, Jenny Yeung, Bernd B Zeisig, Nikolay Popov, Ivo J Huijbers, Josephine Barnes, Amanda Wilson, Erdogan Taskesen, Ruud Delwel, Maarten Van Lohuizen
    Abstract:

    Summary BMI1 is required for efficient self-renewal of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). In this study, we investigated whether leukemia-associated fusion proteins, which differ in their ability to activate Hox expression, could initiate leukemia in the absence of BMI1 . AML1-ETO and PLZF-RARα, which do not activate Hox , triggered senescence in BMI1 −/− cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and Hoxa9 , readily transformed BMI1 −/− cells. MLL-AF9 could not initiate leukemia in BMI1 −/− Hoxa9 −/− mice, which have further compromised HSC functions. But either gene could restore the ability of MLL-AF9 to establish LSCs in the double null background. As reported for BMI1, Hoxa9 regulates expression of p16 Ink4a /p19 ARF locus and could overcome senescence induced by AML1-ETO. Together, these results reveal an important functional interplay between MLL/Hox and BMI1 in regulating cellular senescence for LSC development, suggesting that a synergistic targeting of both molecules is required to eradicate a broader spectrum of LSCs.

  • BMI1 is required for Hedgehog pathway-driven medulloblastoma expansion.
    Neoplasia, 2008
    Co-Authors: Lowell Evan Michael, Maarten Van Lohuizen, Bart A. Westerman, Alexandre N. Ermilov, Aiqin Wang, Jennifer Ferris, Marleen Blom, David W. Ellison, Andrzej A. Dlugosz
    Abstract:

    Inappropriate Hedgehog (Hh) signaling underlies development of a subset of medulloblastomas, and tumors with elevated HH signaling activity express the stem cell self-renewal gene BMI1 . To test whether BMI1 is required for Hh-driven medulloblastoma development, we varied BMI1 gene dosage in transgenic mice expressing an oncogenic Hh effector, SmoA1 , driven by a glial fibrillary acidic protein (GFAP) promoter. Whereas 100% of SmoA1; BMI1 +/+ or SmoA1;BMI1 +/- mice examined between postnatal (P) days 14 and 26 had typical medulloblastomas ( N = 29), tumors were not detected in any of the SmoA1;BMI1 -/- animals examined ( N = 6). Instead, small ectopic collections of cells were present in the region of greatest tumor load in SmoA1 animals, suggesting that medulloblastomas were initiated but failed to undergo expansion into frank tumors. Cells within these BMI1 -/- lesions expressed SmoA1 but were largely nonproliferative, in contrast to cells in BMI1 +/+ tumors (6.2% vs 81.9% PCNA-positive, respectively). Ectopic cells were negative for the progenitor marker nestin, strongly GFAP-positive, and highly apoptotic, relative to BMI1 +/+ tumor cells (29.6% vs 6.3% TUNEL-positive). The alterations in proliferation and apoptosis in SmoA1;BMI1 -/- ectopic cells are associated with reduced levels of Cyclin D1 and elevated expression of cyclin-dependent kinase inhibitor p19 Arf , two inversely regulated downstream targets of BMI1. These data provide the first demonstration that BMI1 is required for spontaneous de novo development of a solid tumor arising in the brain, suggest a crucial role for BMI1-dependent, nestin-expressing progenitor cells in medulloblastoma expansion, and implicate BMI1 as a key factor required for Hh pathway-driven tumorigenesis.

Mark J. Alkema - One of the best experts on this subject based on the ideXlab platform.

  • Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu BMI1 transgenic mice require the BMI1 RING finger
    Oncogene, 1997
    Co-Authors: Mark J. Alkema, Heinz Jacobs, Maarten Van Lohuizen, Anton Berns
    Abstract:

    Perturbation of B and T cell development and predisposition to lymphomagenesis in Eμ Bmi 1 transgenic mice require the BMI1 RING finger

  • pertubation of b and t cell development and predisposition to lymphomagenesis in emu BMI1 transgenic mice require the BMI1 ring finger
    Oncogene, 1997
    Co-Authors: Mark J. Alkema, Heinz Jacobs, Maarten Van Lohuizen, Anton Berns
    Abstract:

    Proviral activation of the BMI1 gene has implicated BMI1 as a collaborator of c-Myc in lymphomagenesis. To determine the effect of BMI1 overexpression on hema- topoiesis and lymphomagenesis transgenic mice were generated that overexpress different forms of the BMI1 protein in their lymphoid compartment. EμBMI1 transgenic mice, overexpressing the wild type BMI1 protein showed a perturbed lymphoid development and were highly susceptible to B and T cell lymphomagenesis. Mutational analysis of the BMI1 protein demonstrated that the conserved N-terminal RING finger and central part of BMI1 are essential for its oncogenic potential whereas the C-terminal Pro-Ser rich region is not required. We have used provirus tagging in the EμBMI1 mice to identify genes that cooperate with BMI1 in lymphomagenesis. MoMLV infection in EμBMI1 transgenic mice accelerated lymphoma development. Proviral activation of the Pim and Myc genes but not the Gfi1 gene were frequently observed in these tumors. These results demonstrate that BMI1 is a potent oncogene and suggest that it plays an important role in early lymphoid development.

  • identification of BMI1 interacting proteins as constituents of a multimeric mammalian polycomb complex
    Genes & Development, 1997
    Co-Authors: Mark J. Alkema, M Bronk, Els Verhoeven, Arie P Otte, L J Van T Veer, A Berns, M Van Lohuizen
    Abstract:

    The Bmil gene has been identified as a mouse Polycomb group (Pc-G) gene implicated in the regulation of Hox gene expression. Here we describe the characterization of a Bmi binding protein Mphl, which shares similarity to Drosophila polyhomeotic. Coimmunoprecipitation experiments indicate that Bmil and Mphl, as well as the Mell8 and M33 proteins described previously, are constituents of a multimeric protein complex in mouse embryos and human cells. A central domain of Bmil interacts with the carboxyl terminus of Mphl, whereas a conserved a-helical domain in the Mphl protein is required for its homodimerization. Transgenic mice overexpressing various mutant Bmil proteins demonstrate that the central domain of Bmil is required for the induction of anterior transformations of the axial skeleton. Bmil, M33, and Mphl show an overlapping speckled distribution in interphase nuclei. These data provide molecular evidence for the existence of a mammalian Polycomb complex.

Hiromitsu Nakauchi - One of the best experts on this subject based on the ideXlab platform.

  • the polycomb gene product BMI1 contributes to the maintenance of tumor initiating side population cells in hepatocellular carcinoma
    Cancer Research, 2008
    Co-Authors: Tetsuhiro Chiba, Atsunori Saraya, Satoru Miyagi, Yohei Morita, Ryutaro Aoki, Atsuyoshi Seki, Yutaka Yonemitsu, Osamu Yokosuka, Hideki Taniguchi, Hiromitsu Nakauchi
    Abstract:

    Side population (SP) cell analysis and sorting have been successfully applied to hepatocellular carcinoma (HCC) cell lines to identify a minor cell population with cancer stem cell properties. However, the molecular mechanisms operating in SP cells remain unclear. The polycomb gene product BMI1 plays a central role in the self-renewal of somatic stem cells in a variety of tissues and organs and seems to be implicated in tumor development. In this study, we determined the critical role of BMI1 in the maintenance of cancer stem cells with the SP phenotype in HCC cell lines. BMI1 was preferentially expressed in SP cells in Huh7 and PLC/PRF/5 HCC cells compared with the corresponding non-SP cells. Lentiviral knockdown of BMI1 considerably decreased the number of SP cells in both Huh7 and PLC/PRF/5 cells. Long-term culture of purified SP cells resulted in a drastic reduction in the SP subpopulation upon the BMI1 knockdown, indicating that BMI1 is required for the self-renewal of SP cells in culture. More importantly, the BMI1 knockdown abolished the tumor-initiating ability of SP cells in nonobese diabetic/severe combined immunodeficiency mice. Derepression of the INK4A and ARF genes that are major targets for BMI1 was not necessarily associated with impaired self-renewal of SP cells caused by BMI1 knockdown. In conclusion, our findings define an important role for BMI1 in the maintenance of tumor-initiating SP cells in HCC. BMI1 might be a novel therapeutic target for the eradication of cancer stem cells in HCC.

  • differential impact of ink4a and arf on hematopoietic stem cells and their bone marrow microenvironment in BMI1 deficient mice
    Journal of Experimental Medicine, 2006
    Co-Authors: Maarten Van Lohuizen, Hideyuki Oguro, Atsushi Iwama, Yohei Morita, Takehiko Kamijo, Hiromitsu Nakauchi
    Abstract:

    The polycomb group (PcG) protein BMI1 plays an essential role in the self-renewal of hematopoietic and neural stem cells. Derepression of the Ink4a/Arf gene locus has been largely attributed to BMI1-deficient phenotypes in the nervous system. However, its role in hematopoietic stem cell (HSC) self-renewal remained undetermined. In this study, we show that derepressed p16Ink4a and p19Arf in BMI1-deficient mice were tightly associated with a loss of self-renewing HSCs. The deletion of both Ink4a and Arf genes substantially restored the self-renewal capacity of BMI1−/− HSCs. Thus, BMI1 regulates HSCs by acting as a critical failsafe against the p16Ink4a- and p19Arf-dependent premature loss of HSCs. We further identified a novel role for BMI1 in the organization of a functional bone marrow (BM) microenvironment. The BM microenvironment in BMI1−/− mice appeared severely defective in supporting hematopoiesis. The deletion of both Ink4a and Arf genes did not considerably restore the impaired BM microenvironment, leading to a sustained postnatal HSC depletion in BMI1−/−Ink4a-Arf−/− mice. Our findings unveil a differential role of derepressed Ink4a and Arf on HSCs and their BM microenvironment in BMI1-deficient mice. Collectively, BMI1 regulates self-renewing HSCs in both cell-autonomous and nonautonomous manners.

Atsushi Iwama - One of the best experts on this subject based on the ideXlab platform.

  • BMI1 is essential for leukemic reprogramming of myeloid progenitor cells
    Leukemia, 2011
    Co-Authors: Jin Yuan, Masahiro Takeuchi, Hideyuki Oguro, Masamitsu Negishi, Hitoshi Ichikawa, Atsushi Iwama
    Abstract:

    The polycomb group (PcG) proteins, particularly BMI1, have an essential role in maintaining the self-renewing capacity of leukemic stem cells (LSCs). Although one of their major targets in LSCs is known to be the Ink4a/Arf tumor suppressor gene locus, the role of PcG proteins in the leukemic reprogramming of target cells into LSCs is not well characterized. In this study, BMI1−/− granulocyte/macrophage progenitors (GMPs) were transformed with the leukemic fusion gene MLL–AF9. Although BMI1 was not essential to the immortalization of GMPs in vitro, BMI1−/− cells showed enhanced differentiation and retained less LSCs. A number of genes were derepressed in the absence of BMI1 including potential tumor suppressor genes. Transplantation assays demonstrated that BMI1 was indispensable for the development of leukemia in vivo and deletion of both the Ink4a and Arf genes only partially restored the leukemogenic capacity of BMI1−/− LSCs. Of note, the complementation of immortalized BMI1−/−Ink4a-Arf−/− GMPs with BMI1 failed to restore the expression of the majority of deregulated genes and leukemogenic activity in vivo. These findings indicate that BMI1 is essential for the faithful reprogramming of myeloid progenitors into LSCs and unveil that leukemic fusion genes require PcG proteins exerting an effect in concert to establish LSC-specific transcriptional profiles, which confer full leukemogenic activity on LSCs.

  • BMI1 Confers Stress Resistance to Self-Renewing Hematopoietic Stem Cells.
    Blood, 2010
    Co-Authors: Shunsuke Nakamura, Atsushi Iwama
    Abstract:

    Abstract 1607 The polycomb group (PcG) proteins form chromatin-modifying complexes that implement transcriptional silencing. There are two major PcG complexes, polycomb repressive complex (PRC) 1 and PRC2. PRC1 ubiquitylates histone H2A at lysine 119 and PRC2 trimethylates lysine 27 of histone H3. Among PcG proteins, BMI1, a core component of PRC1, plays an essential role in the self-renewal and maintenance of various kinds of stem cells including hematopoietic stem cells (HSCs), neural stem cells, and leukemic stem cells. We previously reported that forced expression of BMI1 using a BMI1 retrovirus promotes symmetrical cell division of HSCs, resulting in a marked ex vivo expansion of multipotent progenitors and an enhancement of repopulating capacity of HSCs in vivo . However, the impact of overexpression of BMI1 in HSCs remains to be precisely addressed. To this end, we generated a mouse line where BMI1 can be conditionally overexpressed under the control of the Rosa promoter in a tissue-specific fashion by the Cre-LoxP system. We crossed the mice to Tie2-Cre mice ( Tie2-Cre ; Rosa-BMI1 fl/+ ) and induced overexpression of BMI1 in hematopoietic cells in vivo . Real-time PCR analysis demonstrated that expression of BMI1 inpurified bone marrow (BM) c-Kit + Sca-1 + Lineage-marker - (KSL) cells was 6-fold higher in Tie2-Cre ; Rosa-BMI1 fl/+ mice than control Tie2-Cre mice mice. Overexpression of BMI1 did not significantly affect steady state hematopoiesis. The number of HSCs and progenitors (multipotent progenitors, CMPs, GMP, MEPs, and CLPs) and lineage composition (myeloid cells, B cells, and T cells) in BM of Tie2-Cre; Rosa-BMI1 fl/+ mice was not significantly changed compared to those in control mice. We then performed serial transplantation assay. The repopulating capacity of Tie2-Cre; Rosa-BMI1 fl/+ BM cells was comparable to those of the control cells in primary recipients. However, Tie2-Cre; Rosa-BMI1 fl/+ cells retained higher repopulating capacity during serial transplantation compared to those of the control cells. Moreover, ex vivo culture of Tie2-Cre; Rosa-BMI1 fl/+ HSCs for 10 days contained approximately 2-fold more high proliferative potential colony-forming cells (HPP-CFCs; colony diameter>1mm) and colony-forming unit-neutrophil/macrophage/erythroblast/megakaryocyte (CFU-nmEM) which retain multi-lineage differentiation potential along myeloid lineage than the control. Of note, cells in ex vivo culture of Tie2-Cre; Rosa-BMI1 fl/+ HSCs exhibited significantly augmented repopulating capacity in recipient mice and we are now engaged in competitive repopulation unit (CRU) assays to determine the net HSC expansion by overexpression of BMI1 during ex vivo culture. These results indicate that overexpression of BMI1 confers stress resistance to HSCs during ex vivo culture and serial transplantation. Our findings also provide BMI1 as a potential target for efficient manipulation of HSCs ex vivo . Disclosures: No relevant conflicts of interest to declare.

  • BMI1 Is Essential for Leukemic Reprogramming of Myeloid Progenitor Cells.
    Blood, 2009
    Co-Authors: Jin Yuan, Masahiro Takeuchi, Hideyuki Oguro, Masamitsu Negishi, Hitoshi Ichikawa, Atsushi Iwama
    Abstract:

    Abstract 1423 Poster Board I-446 The polycomb group (PcG) protein BMI1 plays an essential role in the maintenance of self-renewing hematopoietic stem cells (HSCs). Derepressed p16 Ink4a and p19 Arf are tightly associated with a loss of self-renewing capacity of HSCs in BMI1 -deficient mice. Deletion of both Ink4a and Arf genes substantially restores the self-renewal capacity of BMI1 −/− HSCs. Thus, BMI1 maintains HSCs by acting as a critical failsafe against the p16 Ink4a - and p19 Arf -dependent senescence pathway. Meanwhile, BMI1 was originally identified as a collaborating oncogene in the induction of lymphoma and was subsequently reported to be overexpressed in various human cancers including leukemia. Recent studies have demonstrated that PcG proteins bind to multiple regions of the genome and regulate a bunch of target genes. Therefore, we asked whether BMI1 is essential for leukemic stem cells (LSCs) and tried to identify critical target genes for BMI1 other than Ink4a and Arf in leukemia. We expressed the MLL-AF9 leukemic fusion gene in purified Lin − Sca-1 − c-Kit + CD34 + FcγRII/ III hi granulocyte/macrophage progenitors (GMPs) from wild-type, BMI1 −/− , Ink4a-Arf −/− , and BMI1 −/− Ink4a-Arf −/− mice and performed in vitro myeloid progenitor replating assay. GMPs from 4 different genetic backgrounds were all immortalized in vitro , although BMI1 -deficient cells showed a slightly decreased replating efficiency. We then infused the immortalized cells into lethally irradiated recipient mice. Mice infused with wild-type and Ink4a-Arf −/− cells developed acute myelogenous leukemia (AML) at 30 to 60 days after infusion. Mice infused with BMI1 −/− cells did not develop leukemia at all. While a significant portion of mice infused with BMI1 −/− Ink4a-Arf −/− cells developed AML, although they took much longer time compared to those mice infused with wild-type and Ink4a-Arf −/− cells. These results indicate that as in HSCs, the Ink4a /Arf locus is one of the major targets for BMI1 in leukemogenesis. In order to find unknown targets of BMI1 in LSCs, we compared gene expression profiles of purified c-Kit hi FcRγII/III hi CD34 + cells from Ink4a-Arf −/− and BMI1 −/− Ink4a-Arf −/− immortalized cells. We found that the loss of BMI1 did not affect the induction of MLL-AF9 target gene expression. By contrast, a number of genes were derepressed in the absence of BMI1. Among these, Tbx15 , a transcriptional co-repressor gene, appeared to be regulated by BMI1 and a potential tumor suppressor gene in the development of leukemia. Of interest, the majority of derepressed target genes in transformed BMI1 −/− Ink4a-Arf −/− cells, including Tbx15, remained unchanged by re-expression of BMI1. Correspondingly, re-introduction of BMI1 to transformed BMI1 −/− Ink4a-Arf −/− cells failed to rescue their compromised leukemogenic activity in vivo . Our findings suggest that BMI1 is required for faithful epigenetic reprogramming of myeloid progenitors into LSCs by leukemic fusions and contributes to establish LSC-specific transcriptional profiles to confer full leukemogenic activity on LSCs. Disclosures: No relevant conflicts of interest to declare.

  • BMI1 regulates memory cd4 t cell survival via repression of the noxa gene
    Journal of Experimental Medicine, 2008
    Co-Authors: Masakatsu Yamashita, Atsushi Iwama, Makoto Kuwahara, Akane Suzuki, Kiyoshi Hirahara, Ryo Shinnaksu, Hiroyuki Hosokawa, Akihiro Hasegawa, Shinichiro Motohashi, Toshinori Nakayama
    Abstract:

    The maintenance of memory T cells is central to the establishment of immunological memory, although molecular details of the process are poorly understood. In the absence of the polycomb group (PcG) gene BMI1 , the number of memory CD4 + T helper (Th)1/Th2 cells was reduced significantly. Enhanced cell death of BMI1 −/− memory Th2 cells was observed both in vivo and in vitro. Among various proapoptotic genes that are regulated by BMI1, the expression of proapoptotic BH3-only protein Noxa was increased in BMI1 −/− effector Th1/Th2 cells. The generation of memory Th2 cells was restored by the deletion of Noxa , but not by Ink4a and Arf . Direct binding of BMI1 to the Noxa gene locus was accompanied by histone H3-K27 methylation. The recruitment of other PcG gene products and Dnmt1 to the Noxa gene was highly dependent on the expression of BMI1. In addition, BMI1 was required for DNA CpG methylation of the Noxa gene. Moreover, memory Th2-dependent airway inflammation was attenuated substantially in the absence of BMI1. Thus, BMI1 controls memory CD4 + Th1/Th2 cell survival and function through the direct repression of the Noxa gene.

  • differential impact of ink4a and arf on hematopoietic stem cells and their bone marrow microenvironment in BMI1 deficient mice
    Journal of Experimental Medicine, 2006
    Co-Authors: Maarten Van Lohuizen, Hideyuki Oguro, Atsushi Iwama, Yohei Morita, Takehiko Kamijo, Hiromitsu Nakauchi
    Abstract:

    The polycomb group (PcG) protein BMI1 plays an essential role in the self-renewal of hematopoietic and neural stem cells. Derepression of the Ink4a/Arf gene locus has been largely attributed to BMI1-deficient phenotypes in the nervous system. However, its role in hematopoietic stem cell (HSC) self-renewal remained undetermined. In this study, we show that derepressed p16Ink4a and p19Arf in BMI1-deficient mice were tightly associated with a loss of self-renewing HSCs. The deletion of both Ink4a and Arf genes substantially restored the self-renewal capacity of BMI1−/− HSCs. Thus, BMI1 regulates HSCs by acting as a critical failsafe against the p16Ink4a- and p19Arf-dependent premature loss of HSCs. We further identified a novel role for BMI1 in the organization of a functional bone marrow (BM) microenvironment. The BM microenvironment in BMI1−/− mice appeared severely defective in supporting hematopoiesis. The deletion of both Ink4a and Arf genes did not considerably restore the impaired BM microenvironment, leading to a sustained postnatal HSC depletion in BMI1−/−Ink4a-Arf−/− mice. Our findings unveil a differential role of derepressed Ink4a and Arf on HSCs and their BM microenvironment in BMI1-deficient mice. Collectively, BMI1 regulates self-renewing HSCs in both cell-autonomous and nonautonomous manners.

Hideyuki Oguro - One of the best experts on this subject based on the ideXlab platform.

  • BMI1 is essential for leukemic reprogramming of myeloid progenitor cells
    Leukemia, 2011
    Co-Authors: Jin Yuan, Masahiro Takeuchi, Hideyuki Oguro, Masamitsu Negishi, Hitoshi Ichikawa, Atsushi Iwama
    Abstract:

    The polycomb group (PcG) proteins, particularly BMI1, have an essential role in maintaining the self-renewing capacity of leukemic stem cells (LSCs). Although one of their major targets in LSCs is known to be the Ink4a/Arf tumor suppressor gene locus, the role of PcG proteins in the leukemic reprogramming of target cells into LSCs is not well characterized. In this study, BMI1−/− granulocyte/macrophage progenitors (GMPs) were transformed with the leukemic fusion gene MLL–AF9. Although BMI1 was not essential to the immortalization of GMPs in vitro, BMI1−/− cells showed enhanced differentiation and retained less LSCs. A number of genes were derepressed in the absence of BMI1 including potential tumor suppressor genes. Transplantation assays demonstrated that BMI1 was indispensable for the development of leukemia in vivo and deletion of both the Ink4a and Arf genes only partially restored the leukemogenic capacity of BMI1−/− LSCs. Of note, the complementation of immortalized BMI1−/−Ink4a-Arf−/− GMPs with BMI1 failed to restore the expression of the majority of deregulated genes and leukemogenic activity in vivo. These findings indicate that BMI1 is essential for the faithful reprogramming of myeloid progenitors into LSCs and unveil that leukemic fusion genes require PcG proteins exerting an effect in concert to establish LSC-specific transcriptional profiles, which confer full leukemogenic activity on LSCs.

  • BMI1 Is Essential for Leukemic Reprogramming of Myeloid Progenitor Cells.
    Blood, 2009
    Co-Authors: Jin Yuan, Masahiro Takeuchi, Hideyuki Oguro, Masamitsu Negishi, Hitoshi Ichikawa, Atsushi Iwama
    Abstract:

    Abstract 1423 Poster Board I-446 The polycomb group (PcG) protein BMI1 plays an essential role in the maintenance of self-renewing hematopoietic stem cells (HSCs). Derepressed p16 Ink4a and p19 Arf are tightly associated with a loss of self-renewing capacity of HSCs in BMI1 -deficient mice. Deletion of both Ink4a and Arf genes substantially restores the self-renewal capacity of BMI1 −/− HSCs. Thus, BMI1 maintains HSCs by acting as a critical failsafe against the p16 Ink4a - and p19 Arf -dependent senescence pathway. Meanwhile, BMI1 was originally identified as a collaborating oncogene in the induction of lymphoma and was subsequently reported to be overexpressed in various human cancers including leukemia. Recent studies have demonstrated that PcG proteins bind to multiple regions of the genome and regulate a bunch of target genes. Therefore, we asked whether BMI1 is essential for leukemic stem cells (LSCs) and tried to identify critical target genes for BMI1 other than Ink4a and Arf in leukemia. We expressed the MLL-AF9 leukemic fusion gene in purified Lin − Sca-1 − c-Kit + CD34 + FcγRII/ III hi granulocyte/macrophage progenitors (GMPs) from wild-type, BMI1 −/− , Ink4a-Arf −/− , and BMI1 −/− Ink4a-Arf −/− mice and performed in vitro myeloid progenitor replating assay. GMPs from 4 different genetic backgrounds were all immortalized in vitro , although BMI1 -deficient cells showed a slightly decreased replating efficiency. We then infused the immortalized cells into lethally irradiated recipient mice. Mice infused with wild-type and Ink4a-Arf −/− cells developed acute myelogenous leukemia (AML) at 30 to 60 days after infusion. Mice infused with BMI1 −/− cells did not develop leukemia at all. While a significant portion of mice infused with BMI1 −/− Ink4a-Arf −/− cells developed AML, although they took much longer time compared to those mice infused with wild-type and Ink4a-Arf −/− cells. These results indicate that as in HSCs, the Ink4a /Arf locus is one of the major targets for BMI1 in leukemogenesis. In order to find unknown targets of BMI1 in LSCs, we compared gene expression profiles of purified c-Kit hi FcRγII/III hi CD34 + cells from Ink4a-Arf −/− and BMI1 −/− Ink4a-Arf −/− immortalized cells. We found that the loss of BMI1 did not affect the induction of MLL-AF9 target gene expression. By contrast, a number of genes were derepressed in the absence of BMI1. Among these, Tbx15 , a transcriptional co-repressor gene, appeared to be regulated by BMI1 and a potential tumor suppressor gene in the development of leukemia. Of interest, the majority of derepressed target genes in transformed BMI1 −/− Ink4a-Arf −/− cells, including Tbx15, remained unchanged by re-expression of BMI1. Correspondingly, re-introduction of BMI1 to transformed BMI1 −/− Ink4a-Arf −/− cells failed to rescue their compromised leukemogenic activity in vivo . Our findings suggest that BMI1 is required for faithful epigenetic reprogramming of myeloid progenitors into LSCs by leukemic fusions and contributes to establish LSC-specific transcriptional profiles to confer full leukemogenic activity on LSCs. Disclosures: No relevant conflicts of interest to declare.

  • differential impact of ink4a and arf on hematopoietic stem cells and their bone marrow microenvironment in BMI1 deficient mice
    Journal of Experimental Medicine, 2006
    Co-Authors: Maarten Van Lohuizen, Hideyuki Oguro, Atsushi Iwama, Yohei Morita, Takehiko Kamijo, Hiromitsu Nakauchi
    Abstract:

    The polycomb group (PcG) protein BMI1 plays an essential role in the self-renewal of hematopoietic and neural stem cells. Derepression of the Ink4a/Arf gene locus has been largely attributed to BMI1-deficient phenotypes in the nervous system. However, its role in hematopoietic stem cell (HSC) self-renewal remained undetermined. In this study, we show that derepressed p16Ink4a and p19Arf in BMI1-deficient mice were tightly associated with a loss of self-renewing HSCs. The deletion of both Ink4a and Arf genes substantially restored the self-renewal capacity of BMI1−/− HSCs. Thus, BMI1 regulates HSCs by acting as a critical failsafe against the p16Ink4a- and p19Arf-dependent premature loss of HSCs. We further identified a novel role for BMI1 in the organization of a functional bone marrow (BM) microenvironment. The BM microenvironment in BMI1−/− mice appeared severely defective in supporting hematopoiesis. The deletion of both Ink4a and Arf genes did not considerably restore the impaired BM microenvironment, leading to a sustained postnatal HSC depletion in BMI1−/−Ink4a-Arf−/− mice. Our findings unveil a differential role of derepressed Ink4a and Arf on HSCs and their BM microenvironment in BMI1-deficient mice. Collectively, BMI1 regulates self-renewing HSCs in both cell-autonomous and nonautonomous manners.