1. Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG
- Author
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Balakrishnan, Ilango, Danis, Etienne, Pierce, Angela, Madhavan, Krishna, Wang, Dong, Dahl, Nathan, Sanford, Bridget, Birks, Diane K, Davidson, Nate, Metselaar, Dennis S, Meel, Michaël Hananja, Lemma, Rakeb, Donson, Andrew, Vijmasi, Trinka, Katagi, Hiroaki, Sola, Ismail, Fosmire, Susan, Alimova, Irina, Steiner, Jenna, Gilani, Ahmed, Hulleman, Esther, Serkova, Natalie J, Hashizume, Rintaro, Hawkins, Cynthia, Carcaboso, Angel M, Gupta, Nalin, Monje, Michelle, Jabado, Nada, Jones, Kenneth, Foreman, Nicholas, Green, Adam, Vibhakar, Rajeev, and Venkataraman, Sujatha
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Rare Diseases ,Genetics ,Stem Cell Research ,Biotechnology ,Cancer ,Brain Disorders ,Stem Cell Research - Nonembryonic - Non-Human ,Brain Cancer ,Aging ,Astrocytoma ,Brain Stem Neoplasms ,Cell Differentiation ,Cell Line ,Tumor ,Cell Proliferation ,Child ,Child ,Preschool ,Chromatin ,Diffuse Intrinsic Pontine Glioma ,Epigenomics ,Female ,Glioma ,Histones ,Humans ,Lysine ,Male ,Mutation ,Neoplasm Recurrence ,Local ,Polycomb Repressive Complex 1 ,BH3 mimetics ,BMI1 ,DIPG ,H3K27M mutant ,H3WT ,PTC 028 ,RNAi screen ,SASP ,senescence ,Bmi1 ,PTC028 ,Medical Physiology ,Biological sciences - 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.
- Published
- 2020