Bmi1 Controls Tumor Development in an Ink4a/Arf-Independent Manner in a Mouse Model for Glioma

Bruggeman, Sophia W.M.; Hulsman, Danielle; Tanger, Ellen; Buckle, Tessa; Blom, Marleen; Zevenhoven, John; Tellingen, Olaf van; Lohuizen, Maarten van

doi:10.1016/j.ccr.2007.08.032

Cited by 266 publications

(233 citation statements)

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“…Bmi1 is a well-known repressor of p16INK4a and, in some cases, such as in mammalian cells, p14ARF genes (Jacobs et al, 1999;Molofsky et al, 2006). However, several previous reports have indicated that there could be another important Bmi1 target gene, especially in the nervous system, in addition to p16INK4a/p14ARF (Jacobs et al, 1999;Bruggeman et al, 2007). In our study, Bmi1 overexpression accelerated the proliferation of several NB cell lines, although p14ARF/ p16INK4a repression was not so obvious (Figure 4).…”

Section: Mycn-induced Bmi1 Represses Tumor Suppressors H Ochiai Et Alcontrasting

confidence: 43%

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

et al. 2010

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Recent advances in neuroblastoma (NB) research addressed that epigenetic alterations such as hypermethylation of promoter sequences, with consequent silencing of tumor-suppressor genes, can have significant roles in the tumorigenesis of NB. However, the exact role of epigenetic alterations, except for DNA hypermethylation, remains to be elucidated in NB research. In this paper, we clarified the direct binding of MYCN to Bmi1 promoter and upregulation of Bmi1 transcription by MYCN. Mutation introduction into an MYCN binding site in the Bmi1 promoter suggests that MYCN has more important roles in the transcription of Bmi1 than E2F-related Bmi1 regulation. A correlation between MYCN and polycomb protein Bmi1 expression was observed in primary NB tumors. Expression of Bmi1 resulted in the acceleration of proliferation and colony formation in NB cells. Bmi1-related inhibition of NB cell differentiation was confirmed by neurite extension assay and analysis of differentiation marker molecules. Intriguingly, the above-mentioned Bmi1-related regulation of the NB cell phenotype seems not to be mediated only by p14ARF/p16INK4a in NB cells. Expression profiling analysis using a tumor-specific cDNA microarray addressed the Bmi1-dependent repression of KIF1Bb and TSLC1, which have important roles in predicting the prognosis of NB. Chromatin immunoprecipitation assay showed that KIF1Bb and TSLC1 are direct targets of Bmi1 in NB cells. These findings suggest that MYCN induces Bmi1 expression, resulting in the repression of tumor suppressors through Polycomb group genemediated epigenetic chromosome modification. NB cell proliferation and differentiation seem to be partially dependent on the MYCN/Bmi1/tumor-suppressor pathways.

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Section: Mycn-induced Bmi1 Represses Tumor Suppressors H Ochiai Et Alcontrasting

confidence: 43%

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

et al. 2010

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Section: Chromatin Modifiers In Aging Stem Cellsmentioning

confidence: 78%

“…Consistently, BMI1 also controls the differentiation potential of adult NSCs (Zencak et al, 2005;Bruggeman et al, 2007). In young adult mice, constitutive deletion of Bmi1 triggers increased glial cell production in vivo (Zencak et al, 2005) and decreased neurogenic capacity of cultured adult NSCs after serial passaging (Bruggeman et al, 2007). This increase in astrocytes phenocopies the increase in astrocyte production known to occur in the brain during aging (Bondolfi et al, 2004), raising the possibility that altered activity of BMI1 during aging contributes to a loss of stem cell multipotency.…”

Section: Chromatin Modifiers In Aging Stem Cellsmentioning

confidence: 85%

“…For example, PcG group proteins BMI1 and EZH2 have both been strongly implicated in cancer progression and are overexpressed in a variety of cancer types (Valk-Lingbeek et al, 2004). BMI1 is required for proliferation of leukemia stem cells (Lessard and Sauvageau, 2003) and transformation in a mouse model of glioma (Bruggeman et al, 2007). Transcriptional regulators of stem cell chromatin have likewise been implicated in promoting neoplasm.…”

Section: Chromatin Aging Stem Cells and Tumor Developmentmentioning

confidence: 99%

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Epigenetic regulation of aging stem cells

2011

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“…Of interest, an Ink4a/Arf-independent contribution of Bmi1 to not only self-renewal in neural stem cells but also tumorigenesis in a mouse model for glioma has been reported. 27,28 The current in vivo transplant assays ascertained that Bmi1-transduced Ink4a/Arf À/À Dlk þ cells but not control Ink4a/Arf À/À Dlk þ cells acquire tumorigenic potential. Bmi1-transduced Ink4a/Arf À/À Dlk þ cells showed an augmented self-renewal capability as evident from the higher replating efficiency in the single cell-sorting analysis compared to Ink4a/Arf À/À Dlk þ cells.…”

Section: Discussionmentioning

confidence: 98%

Bmi1 Promotes Hepatic Stem Cell Expansion and Tumorigenicity in Both Ink4a/Arf -Dependent and -Independent Manners in Mice†

et al. 2010

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We previously reported that forced expression of Bmi1 (B lymphoma Moloney murine leukemia virus insertion region 1 homolog) in murine hepatic stem/progenitor cells purified from fetal liver enhances their self-renewal and drives cancer initiation. In the present study, we examined the contribution of the Ink4a/Arf tumor suppressor gene locus, one of the major targets of Bmi1, to stem cell expansion and cancer initiation. Bmi1 2/2 Deltalike protein (Dlk) 1 hepatic stem/progenitor cells showed de-repression of the Ink4a/Arf locus and displayed impaired growth activity. In contrast, Ink4a/Arf 2/2 Dlk 1 cells gave rise to considerably larger colonies containing a greater number of bipotent cells than wild-type Dlk 1 cells. Although Ink4a/Arf 2/2 Dlk 1 cells did not initiate tumors in recipient nonobese diabetic/severe combined immunodeficiency mice, enforced expression of Bmi1 in Ink4a/Arf 2/2 Dlk 1 cells further augmented their self-renewal capacity and resulted in tumor formation in vivo. Microarray analyses successfully identified five downregulated genes as candidate downstream targets for Bmi1 in hepatic stem/progenitor cells. Of these genes, enforced expression of sex determining region Y-box 17 (Sox17) in Dlk 1 cells strongly suppressed colony propagation and tumor growth. Conclusion: These results indicate that repression of targets of Bmi1 other than the Ink4a/Arf locus plays a crucial role in the oncogenic transformation of hepatic stem/progenitor cells. Functional analyses of Bmi1 target genes would be of importance to elucidate the molecular machinery underlying hepatic stem cell system and explore therapeutic approaches for the eradication of liver cancer stem cells.

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Bmi1 Controls Tumor Development in an Ink4a/Arf-Independent Manner in a Mouse Model for Glioma

Cited by 266 publications

References 57 publications

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

Epigenetic regulation of aging stem cells

Bmi1 Promotes Hepatic Stem Cell Expansion and Tumorigenicity in Both Ink4a/Arf -Dependent and -Independent Manners in Mice†

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