Cell Reports (Oct 2020)

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 Hananja Meel,
  • Rakeb Lemma,
  • Andrew Donson,
  • Trinka Vijmasi,
  • Hiroaki Katagi,
  • Ismail Sola,
  • Susan Fosmire,
  • Irina Alimova,
  • Jenna Steiner,
  • Ahmed Gilani,
  • Esther 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

Journal volume & issue
Vol. 33, no. 3
p. 108286

Abstract

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Summary: 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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