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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)108286
JournalCell reports
Volume33
Issue number3
DOIs
Publication statusPublished - 20 Oct 2020

Keywords

  • Aging/genetics
  • Astrocytoma/genetics
  • Brain Stem Neoplasms/drug therapy
  • Cell Differentiation/genetics
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Child
  • Child, Preschool
  • Chromatin/genetics
  • Diffuse Intrinsic Pontine Glioma/drug therapy
  • Epigenomics
  • Female
  • Glioma/drug therapy
  • Histones/metabolism
  • Humans
  • Lysine/metabolism
  • Male
  • Mutation
  • Neoplasm Recurrence, Local/drug therapy
  • Polycomb Repressive Complex 1/antagonists & inhibitors

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