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Maarten Van Lohuizen – 1st expert 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


    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


    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


    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.

Mark J. Alkema – 2nd expert 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


    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


    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


    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 – 3rd expert 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


    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, Atsushi Iwama, Hideyuki Oguro, Yohei Morita, Takehiko Kamijo, Hiromitsu Nakauchi


    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.