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

Ilango Balakrishnan | Zendy; Etienne Danis | Zendy; Angela Pierce | Zendy; Krishna Madhavan | Zendy; Dong Wang | Zendy; Nathan Dahl | Zendy; Sanford Bridget | Zendy; Diane K. Birks | Zendy; Nate Davidson | Zendy; Dennis S. Metselaar | Zendy; Michaël H. Meel | Zendy; Rakeb Lemma | Zendy; Andrew M. Donson | Zendy; Trinka Vijmasi | Zendy; Hiroaki Katagi | Zendy; Ismail Sola | Zendy; Susan Fosmire | Zendy; Irina Alimova | Zendy; Jenna Steiner | Zendy; Ahmed Gilani | Zendy; Esther Hulleman | Zendy; Natalie J. Serkova | Zendy; Rintaro Hashizume | Zendy; Cynthia Hawkins | Zendy; Ángel M. Carcaboso | Zendy; Nalin Gupta | Zendy; Michelle Monje | Zendy; Nada Jabado | Zendy; Kenneth L. Jones | Zendy; Nicholas K. Foreman | Zendy; Adam Green | Zendy; Rajeev Vibhakar | Zendy; Sujatha Venkataraman | Zendy

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

Author(s) -

Ilango Balakrishnan,

Etienne Danis,

Angela Pierce,

Krishna Madhavan,

Dong Wang,

Nathan Dahl,

Sanford Bridget,

Diane K. Birks,

Nate Davidson,

Dennis S. Metselaar,

Michaël H. Meel,

Rakeb Lemma,

Andrew M. Donson,

Trinka Vijmasi,

Hiroaki Katagi,

Ismail Sola,

Susan Fosmire,

Irina Alimova,

Jenna Steiner,

Ahmed Gilani,

Esther Hulleman,

Natalie J. Serkova,

Rintaro Hashizume,

Cynthia Hawkins,

Ángel M. Carcaboso,

Nalin Gupta,

Michelle Monje,

Nada Jabado,

Kenneth L. Jones,

Nicholas K. Foreman,

Adam Green,

Rajeev Vibhakar,

Sujatha Venkataraman

Publication year - 2020

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2020.108286

Subject(s) - bmi1 , epigenomics , senescence , cancer research , biology , chromatin , phenotype , rna interference , histone , microbiology and biotechnology , stem cell , genetics , gene expression , gene , dna methylation , rna

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.

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