BMI1 Sustains Human Glioblastoma Multiforme Stem Cell Renewal

Abdouh, Mohamed; Facchino, Sabrina; Chatoo, Wassim; Balasingam, Vijayabalan; Ferreira, José; Bernier, Gilbert

doi:10.1523/jneurosci.0968-09.2009

Cited by 273 publications

(239 citation statements)

References 58 publications

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“…[36][37][38] Neural stem and progenitor cells are in particular characterised by a short G1 cell cycle phase and growing evidence suggests a crucial role for lengthening of G1 phase in differentiation. 27 In line with this hypothesis, a number of experiments in GSCs describe co-occurrence of induced differentiation and reduced proliferation, 16,34,39 in particular by the accumulation of cells in G1/G0 cell cycle phase. 15,40 In agreement with these findings, ENPP1 knockdown in GSCs was found to cause a reduction in the proliferation rate and cells were found to accumulate in G1/G0 cell cycle phase.…”

Section: Discussionmentioning

confidence: 83%

“…26 Here we describe an elevated ENPP1 expression in GSCs compared with normal brain extracts and fNSCs. E-NPP1-deficient GSCs are characterised by downregulation of known stem cell markers, such as CD133, LHX2, MSI1, LGR5 and CD15, 4,8,9,34,35 as well as an overall downregulation of stem cell-associated genes as seen by comparison with published stem cell gene signatures. 24,25 Moreover, GFAP and S100 beta, differentiation marker delineating the astrocytic cell lineage, are upregulated upon knockdown of ENPP1 in cultured GSCs.…”

Section: Discussionmentioning

confidence: 99%

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Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

et al. 2014

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Glioblastomas are highly aggressive brain tumours and are characterised by substantial cellular heterogeneity within a single tumour. A sub-population of glioblastoma stem-like cells (GSCs) that shares properties with neural precursor cells has been described, exhibiting resistance to therapy and therefore being considered responsible for the high recurrence rate in glioblastoma. To elucidate the underlying cellular processes we investigated the role of phosphatases in the GSC phenotype, using an in vitro phosphatome-wide RNA interference screen. We identified a set of genes, the knockdown of which induces a significant decrease in the glioma stem cell marker CD133, indicating a role in the glioblastoma stem-like phenotype. Among these genes, the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) was found to be highly expressed in GSCs compared with normal brain and neural stem cells. Knockdown of ENPP1 in cultured GSCs resulted in an overall downregulation of stem cell-associated genes, induction of differentiation into astrocytic cell lineage, impairment of sphere formation, in addition to increased cell death, accumulation of cells in G1/G0 cell cycle phase and sensitisation to chemotherapeutic treatment. Genome-wide gene expression analysis and nucleoside and nucleotide profiling revealed that knockdown of ENPP1 affects purine and pyrimidine metabolism, suggesting a link between ENPP1 expression and a balanced nucleoside-nucleotide pool in GSCs. The phenotypic changes in E-NPP1-deficient GSCs are assumed to be a consequence of decreased transcriptional function of E2F1. Together, these results reveal that E-NPP1, by acting upstream of E2F1, is indispensable for the maintenance of GSCs in vitro and hence required to keep GSCs in an undifferentiated, proliferative state. Glioblastoma, classified by the WHO (World Health Organization) as grade IV astrocytoma, 1 is the most common primary malignant brain tumour in adults. Despite progress in surgical resection, radiation and chemotherapy, glioblastoma remains a deadly disease with a median survival time of about 1 year. 2 One particular therapeutic challenge for glioblastoma treatment is posed by their remarkable intratumoural cellular heterogeneity. Several studies indicate the existence of a highly tumourigenic, sub-population of cancer cells with stemlike characteristics. [3][4][5] There is substantial evidence that these so-called cancer stem cells have inherent chemotherapy and radiation resistance. 6,7 These findings suggest that cancer cells harbouring stem cell-like characteristics are responsible for ineffective therapy, explaining high recurrence rates despite significant reduction in tumour volume. Glioblastoma stem-like cells (GSCs) share properties with neural precursor cells, such as a capacity for self-renewal, differentiation and maintained proliferation, as well as stem cell marker expression. 4,5,8,9 GSCs were originally defined by expression of CD133 (Prominin-1) and its extracellular AC133 epitope. 4 Although recent...

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

et al. 2014

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“…These cells express high levels of Bmi1 [30], are particularly resistant to apoptosis [31,32] and have recently been shown to be A2B5þ [33]. Overexpression of Bmi1 in postnatal SVZ NSPC in vitro led to increased self-renewal capacity as observed in embryonic NSPC.…”

Section: Discussionmentioning

confidence: 95%

Conditional Activation of Bmi1 Expression Regulates Self-renewal, Apoptosis, and Differentiation of Neural Stem/Progenitor Cells In Vitro and In Vivo

et al. 2011

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The Polycomb group protein Bmi1 is a key regulator of self-renewal of embryonic and adult central nervous system stem cells, and its overexpression has been shown to occur in several types of brain tumors. In a Cre/LoxPbased conditional transgenic mouse model, we show that fine-tuning of Bmi1 expression in embryonic neural stem cell (NSC) is sufficient to increase their proliferation and self-renewal potential both in vitro and in vivo. This is linked to downregulation of both the ink4a/ARF and the p21/Foxg1 axes. However, increased and ectopic proliferation induced by overexpression of Bmi1 in progenitors committed toward a neuronal lineage during embryonic cortical development, triggers apoptosis through a survivin-mediated mechanism and leads to reduced brain size.

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“…To test whether this correlated with alterations in the subnuclear distribution of heterochromatin proteins, we performed cellular fractionation experiments and where the SDSsoluble fraction is thought to be highly enriched for constitutive heterochromatin proteins (11,60). In control cells, BMI1 was detected in the 450 nM NaCl and SDS fractions (Fig.…”

Section: Severe Heterochromatin and Nuclear Envelope Alterations In Hmentioning

confidence: 99%

The Polycomb Repressive Complex 1 Protein BMI1 Is Required for Constitutive Heterochromatin Formation and Silencing in Mammalian Somatic Cells

Abdouh

Hanna

Hajjar

et al. 2016

Journal of Biological Chemistry

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Background: BMI1 silences the expression of genes located at the facultative heterochromatin. Results: BMI1 is abundant at repetitive genomic regions, including the pericentromeric heterochromatin (PCH), where it is required for compaction and silencing. Conclusion: BMI1 is essential for PCH formation. Significance: BMI1 function at PCH is important to understand how BMI1 regulates genomic stability.

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BMI1 Sustains Human Glioblastoma Multiforme Stem Cell Renewal

Abstract: Glioblastoma multiforme (GBM) is

Cited by 273 publications

References 58 publications

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

Conditional Activation of Bmi1 Expression Regulates Self-renewal, Apoptosis, and Differentiation of Neural Stem/Progenitor Cells In Vitro and In Vivo

The Polycomb Repressive Complex 1 Protein BMI1 Is Required for Constitutive Heterochromatin Formation and Silencing in Mammalian Somatic Cells

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