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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.
Originele taal-2Engels
Pagina's (van-tot)108286
TijdschriftCell reports
Volume33
Nummer van het tijdschrift3
DOI's
StatusGepubliceerd - 20 okt. 2020

Trefwoorden

  • BH3 mimetics
  • BMI1
  • DIPG
  • H3K27M mutant
  • H3WT
  • PTC 028
  • RNAi screen
  • SASP
  • senescence

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