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Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG: Influence Statistics

Expert Impact

Concepts for which they have has direct influence: Cell tumor , Senescent cells , Tumor growth , Brain tumor , Polycomb repressive , Repressive complex , Glioma dipg .

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Ahmedin M Jemal
united states breast cancer addis ababa
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Rebecca L Siegel
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Robert A Weinberg
tumor cells retinoblastoma protein cyclin d1
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Freddie Ian Bray
cancer incidence nordic countries mortality rates
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Jacques Ferlay
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Bert Vogelstein
colorectal cancer somatic mutations tumor dna

Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

Abstract

. Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.