@article{541484472e974c2fae53d461242de91b,
title = "Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG",
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",
author = "Ilango Balakrishnan and Etienne Danis and Angela Pierce and Krishna Madhavan and Dong Wang and Nathan Dahl and Bridget Sanford and Birks, {Diane K.} and Nate Davidson and Metselaar, {Dennis S.} and Meel, {Micha{\"e}l Hananja} and Rakeb Lemma and Andrew Donson and Trinka Vijmasi and Hiroaki Katagi and Ismail Sola and Susan Fosmire and Irina Alimova and Jenna Steiner and Ahmed Gilani and Esther Hulleman and Serkova, {Natalie J.} and Rintaro Hashizume and Cynthia Hawkins and Carcaboso, {Angel M.} and Nalin Gupta and Michelle Monje and Nada Jabado and Kenneth Jones and Nicholas Foreman and Adam Green and Rajeev Vibhakar and Sujatha Venkataraman",
note = "Funding Information: This work was supported by the DOD ( CA 160704 ), the Morgan Adams Foundation , ACS-IRG , the Laya Dance Academy , and the Luke Morin and Marc Jr. Foundations . Thanks to Drs. Mitra and Mulcahy-Levy, Mr. Harris, and Ms. Griesinger (UCD) for suggestions. Thanks to Dr. Masanori and Mr. Bodlak for their help in testing the H3K27M mutation status of cells using droplet PCR. Thanks to Drs. Sidharth and Perumal (University of Nebraska) for their timely help with IHC staining of slides. Thanks to Anitha Ponnuswami (Stanford University) for inputs on culturing DIPG cells. Thanks for research help provided by the Functional Genomics, Histology (especially to Ms. E. Smith, A. Quador, and J. Arnold), Genomics Microarray and Animal Imaging, and University of Colorado Cancer Center core facilities funded by NCI ( P30CA046934 ). Funding Information: This work was supported by the DOD (CA 160704), the Morgan Adams Foundation, ACS-IRG, the Laya Dance Academy, and the Luke Morin and Marc Jr. Foundations. Thanks to Drs. Mitra and Mulcahy-Levy, Mr. Harris, and Ms. Griesinger (UCD) for suggestions. Thanks to Dr. Masanori and Mr. Bodlak for their help in testing the H3K27M mutation status of cells using droplet PCR. Thanks to Drs. Sidharth and Perumal (University of Nebraska) for their timely help with IHC staining of slides. Thanks to Anitha Ponnuswami (Stanford University) for inputs on culturing DIPG cells. Thanks for research help provided by the Functional Genomics, Histology (especially to Ms. E. Smith, A. Quador, and J. Arnold), Genomics Microarray and Animal Imaging, and University of Colorado Cancer Center core facilities funded by NCI (P30CA046934). I.B. S.V. K.M. N. Davidson and A.P. performed in vitro and in vivo experiments. E.D. performed ChIP-seq. I.B. K.M. and R.L. performed the combination index study. D.W. B.S. D.K.B. and K.J. performed bioinformatic analysis. M.M. N.G. A.M.C. C.H. and R.H. provided cell lines. T.V. and A.D. performed the cytokine assay. S.F. made plasmids and viruses. A. Gillani evaluated pathology slides. J.S. and N.J.S. analyzed MRI data. I.S. and I.A. performed the apoptosis assay. E.H. D.S.M. and M.H.M. provided IHC of VUMC samples. N.F. and A. Green served as project advisors. S.V. and R.V. provided ideas, grants, and project leadership. Help with Metascape analysis was provided by N. Dahl CRISPR KO cells were provided by N.J. Figures were made by I.B. and K.M. The manuscript was written by S.V. Manuscript input was given by N. Dahl and E.H. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = oct,
day = "20",
doi = "10.1016/j.celrep.2020.108286",
language = "English (US)",
volume = "33",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}