Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas

  title={Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas},
  author={Carly Leung and Merel Lingbeek and Olga Shakhova and James Liu and Ellen Tanger and Parvin Saremaslani and Maarten van Lohuizen and Silvia Marino},
Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf) tumour suppressors. Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-repression of the ink4a/Arf locus is critically implicated. Here, we show that Bmi1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1-null mice we demonstrate a… 

Bmi1 overexpression in the cerebellar granule cell lineage of mice affects cell proliferation and survival without initiating medulloblastoma formation

BMI1 overexpression in GCP-derived human medulloblastomas probably occurs during later stages of oncogenesis and might serve to enhance tumour cell survival, and data suggest that different levels and timing of Bmi1 overeexpression yield distinct cellular outcomes within the same cellular lineage.

GFAP-Cre-Mediated Transgenic Activation of Bmi1 Results in Pituitary Tumors

Two conditional Bmi1 transgenic models that were crossed with GFAP-Cre mice to activate transgenic expression resulted in pituitary tumors but was insufficient to induce medulloblastoma therefore indicating that the oncogenic function of Bmi 1 depends on regulation of p16INK4A/Rb rather than onregulation of p19ARF/p53.

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance and propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell–cell interaction between the CD133+ Hh receptor cells and theCD133− HH-secreting cells.

Bmi1 is required for Hedgehog pathway-driven medulloblastoma expansion.

The first demonstration that Bmi1 is required for spontaneous de novo development of a solid tumor arising in the brain is provided, and a crucial role for Bmi 1-dependent, nestin-expressing progenitor cells in medulloblastoma expansion is suggested.

p27Kip1, a double-edged sword in Shh-mediated medulloblastoma

The data indicate that the dosage of p27Kip1 plays a role in cell cycle progression and tumor suppression in Shh-mediated medulloblastoma expansion and it is found that mis-localized p27kip1 may play a positive role in motility in medullOBlastoma cells.

Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma

Bmi1 Loss Produces an Increase in Astroglial Cells and a Decrease in Neural Stem Cell Population and Proliferation

Bmi1 is expressed in the germinal zone in vivo and in NSCs as well as in progenitors proliferating in vitro, but not in differentiated cells, and the altered cell pattern of the Bmi1-/- brain shows that in vivo astrocyte precursors can proliferate in the absence of Bmi 1.

Genome-wide analysis of gene expression and alternative splicing in human medulloblastoma

Interestingly, Shh-treated GCPs recapitulated the splicing patterns observed in the tumour samples for six out of the eight genes analysed, suggesting that the preferential expression of specific transcript forms is regulated during normal cerebellar development.

Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice.




Mutations in SUFU predispose to medulloblastoma

It is reported that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele.

Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors

It is reported that sonic hedgehog (Shh) signaling upregulates expression of the proto-oncogene Nmyc in cultured cerebellar granule neuron precursors (CGNPs) in the absence of new protein synthesis.

Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum.

It is demonstrated that loss of function of RB is essential for medulloblastoma development in the mouse and strongly support the hypothesis that medullOBlastomas arise from multipotent precursor cells located in the EGL.

N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation.

N-myc is essential for normal neurogenesis, regulating NPC proliferation, differentiation, and nuclear size, and its effects on proliferation and differentiation appear due, at least in part, to down-regulation of a specific subset of cyclin-dependent kinase inhibitors.

The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus

This work shows that bmi-1-deficient primary mouse embryonic fibroblasts are impaired in progression into the S phase of the cell cycle and undergo premature senescence, and connects transcriptional repression by Polycomb-group proteins with cell-cycle control and senescences.

Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene.

Observations indicate that Mbi-1 plays an important role in morphogenesis during embryonic development and in hematopoiesis throughout pre- and postnatal life and provide the first evidence of functional conservation of a mammalian Polycomb group homolog.

Cerebellar histogenesis is disturbed in mice lacking cyclin D2.

It is suggested that cyclin D2 is required in cerebellum not only for proliferation of the granule cell precursors but also for proper differentiation of granule and stellate interneurons.

Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse

It is shown that the concomitant inactivation of one Pten allele and one or both Cdkn1b alleles accelerates spontaneous neoplastic transformation and incidence of tumors of various histological origins in Pten+/−/CdKn1b−/− mice.

A molecular fingerprint for medulloblastoma.

A group of genes that are central to medulloblastoma tumorigenesis are identified, including sFrp1, Ptc2, and Math1, members of signaling pathways that regulate cerebellar development.