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
Affiliations
- Ilango Balakrishnan
- 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
- Etienne Danis
- 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
- Angela Pierce
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Krishna Madhavan
- 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
- Dong Wang
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Nathan Dahl
- 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
- Bridget Sanford
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Diane K. Birks
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Nate Davidson
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Dennis S. Metselaar
- Princess Máxima Center for Pediatric Oncology, Utrecht and Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- Michaël Hananja Meel
- Princess Máxima Center for Pediatric Oncology, Utrecht and Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- Rakeb Lemma
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Andrew Donson
- 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
- Trinka Vijmasi
- 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
- Hiroaki Katagi
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Ismail Sola
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Susan Fosmire
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Irina Alimova
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Jenna Steiner
- Departments of Radiology, Radiation Oncology, and Anesthesiology, Colorado Animal Imaging Shared Resource (AISR), University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Ahmed Gilani
- Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA
- Esther Hulleman
- Princess Máxima Center for Pediatric Oncology, Utrecht and Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- Natalie J. Serkova
- Departments of Radiology, Radiation Oncology, and Anesthesiology, Colorado Animal Imaging Shared Resource (AISR), University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rintaro Hashizume
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Cynthia Hawkins
- Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Angel M. Carcaboso
- Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Barcelona 08950, Spain
- Nalin Gupta
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
- Michelle Monje
- Departments of Neurology, Neurosurgery, Pediatrics, and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Nada Jabado
- 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
- Kenneth Jones
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Nicholas Foreman
- 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
- Adam Green
- 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
- Rajeev Vibhakar
- 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; Corresponding author
- Sujatha Venkataraman
- 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; Corresponding author
- Journal volume & issue
-
Vol. 33,
no. 3
p. 108286
Abstract
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.
