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 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

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

Group Hulleman

Research output: Contribution to journal › Article › peer-review

44 Citations (Scopus)

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.

Original language	English
Article number	108286
Pages (from-to)	108286
Journal	Cell reports
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2020.108286
Publication status	Published - 20 Oct 2020

Keywords

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

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10.1016/j.celrep.2020.108286

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Balakrishnan, I., Danis, E., Pierce, A., Madhavan, K., Wang, D., Dahl, N., Sanford, B., Birks, D. K., Davidson, N., Metselaar, D. S., Meel, M. H., Lemma, R., Donson, A., Vijmasi, T., Katagi, H., Sola, I., Fosmire, S., Alimova, I., Steiner, J., ... Venkataraman, S. (2020). Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG. Cell reports, 33(3), 108286. Article 108286. https://doi.org/10.1016/j.celrep.2020.108286

@article{3f4357e233014559b603cc90580f997b,

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 = "Aging/genetics, Astrocytoma/genetics, Brain Stem Neoplasms/drug therapy, Cell Differentiation/genetics, Cell Line, Tumor, Cell Proliferation/drug effects, Child, Child, Preschool, Chromatin/genetics, Diffuse Intrinsic Pontine Glioma/drug therapy, Epigenomics, Female, Glioma/drug therapy, Histones/metabolism, Humans, Lysine/metabolism, Male, Mutation, Neoplasm Recurrence, Local/drug therapy, Polycomb Repressive Complex 1/antagonists & inhibitors, 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 H.} 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 = "Published by Elsevier Inc.",

year = "2020",

month = oct,

day = "20",

doi = "10.1016/j.celrep.2020.108286",

language = "English",

volume = "33",

pages = "108286",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

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Balakrishnan, I, Danis, E, Pierce, A, Madhavan, K, Wang, D, Dahl, N, Sanford, B, Birks, DK, Davidson, N, Metselaar, DS , Meel, MH, Lemma, R, Donson, A, Vijmasi, T, Katagi, H, Sola, I, Fosmire, S, Alimova, I, Steiner, J, Gilani, A, Hulleman, E, Serkova, NJ, Hashizume, R, Hawkins, C, Carcaboso, AM, Gupta, N, Monje, M, Jabado, N, Jones, K, Foreman, N, Green, A, Vibhakar, R & Venkataraman, S 2020, 'Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG', Cell reports, vol. 33, no. 3, 108286, pp. 108286. https://doi.org/10.1016/j.celrep.2020.108286

TY - JOUR

T1 - Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

AU - Balakrishnan, Ilango

AU - Danis, Etienne

AU - Pierce, Angela

AU - Madhavan, Krishna

AU - Wang, Dong

AU - Dahl, Nathan

AU - Sanford, Bridget

AU - Birks, Diane K

AU - Davidson, Nate

AU - Metselaar, Dennis S.

AU - Meel, Michaël H.

AU - Lemma, Rakeb

AU - Donson, Andrew

AU - Vijmasi, Trinka

AU - Katagi, Hiroaki

AU - Sola, Ismail

AU - Fosmire, Susan

AU - Alimova, Irina

AU - Steiner, Jenna

AU - Gilani, Ahmed

AU - Hulleman, Esther

AU - Serkova, Natalie J

AU - Hashizume, Rintaro

AU - Hawkins, Cynthia

AU - Carcaboso, Angel M

AU - Gupta, Nalin

AU - Monje, Michelle

AU - Jabado, Nada

AU - Jones, Kenneth

AU - Foreman, Nicholas

AU - Green, Adam

AU - Vibhakar, Rajeev

AU - Venkataraman, Sujatha

N1 - Published by Elsevier Inc.

PY - 2020/10/20

Y1 - 2020/10/20

N2 - 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.

AB - 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.

KW - Aging/genetics

KW - Astrocytoma/genetics

KW - Brain Stem Neoplasms/drug therapy

KW - Cell Differentiation/genetics

KW - Cell Line, Tumor

KW - Cell Proliferation/drug effects

KW - Child

KW - Child, Preschool

KW - Chromatin/genetics

KW - Diffuse Intrinsic Pontine Glioma/drug therapy

KW - Epigenomics

KW - Female

KW - Glioma/drug therapy

KW - Histones/metabolism

KW - Humans

KW - Lysine/metabolism

KW - Male

KW - Mutation

KW - Neoplasm Recurrence, Local/drug therapy

KW - Polycomb Repressive Complex 1/antagonists & inhibitors

KW - BH3 mimetics

KW - BMI1

KW - DIPG

KW - H3K27M mutant

KW - H3WT

KW - PTC 028

KW - RNAi screen

KW - SASP

KW - senescence

UR - http://www.scopus.com/inward/record.url?scp=85092931253&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2020.108286

DO - 10.1016/j.celrep.2020.108286

M3 - Article

C2 - 33086074

SN - 2211-1247

VL - 33

SP - 108286

JO - Cell reports

JF - Cell reports

IS - 3

M1 - 108286

ER -

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

Abstract

Keywords

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