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

doi:10.1016/j.celrep.2020.108286

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

Cell Rep. 2020 Oct 20;33(3):108286. doi: 10.1016/j.celrep.2020.108286.

Authors

Ilango Balakrishnan¹, Etienne Danis¹, Angela Pierce², Krishna Madhavan¹, Dong Wang², Nathan Dahl¹, Bridget Sanford², Diane K Birks², Nate Davidson², Dennis S Metselaar³, Michaël Hananja Meel³, Rakeb Lemma², Andrew Donson¹, Trinka Vijmasi¹, Hiroaki Katagi⁴, Ismail Sola², Susan Fosmire², Irina Alimova², Jenna Steiner⁵, Ahmed Gilani⁶, Esther Hulleman³, Natalie J Serkova⁵, Rintaro Hashizume⁴, Cynthia Hawkins⁷, Angel M Carcaboso⁸, Nalin Gupta⁹, Michelle Monje¹⁰, Nada Jabado¹¹, Kenneth Jones², Nicholas Foreman¹, Adam Green¹, Rajeev Vibhakar¹², Sujatha Venkataraman¹³

Affiliations

¹ Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.
² Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
³ Princess Máxima Center for Pediatric Oncology, Utrecht and Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
⁴ Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁵ Departments of Radiology, Radiation Oncology, and Anesthesiology, Colorado Animal Imaging Shared Resource (AISR), University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁶ Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
⁷ Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁸ Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Barcelona 08950, Spain.
⁹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Departments of Neurology, Neurosurgery, Pediatrics, and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹¹ Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.
¹² Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA. Electronic address: [email protected].
¹³ Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA. Electronic address: [email protected].

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.

Keywords: BH3 mimetics; BMI1; DIPG; H3K27M mutant; H3WT; PTC 028; RNAi screen; SASP; senescence.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

BMI1 protein, human
Chromatin
Histones
Polycomb Repressive Complex 1
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding