SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia Journal Article
| Authors: | Mar, B. G.; Chu, S. H.; Kahn, J. D.; Krivtsov, A. V.; Koche, R.; Castellano, C. A.; Kotlier, J. L.; Zon, R. L.; McConkey, M. E.; Chabon, J.; Chappell, R.; Grauman, P. V.; Hsieh, J. J.; Armstrong, S. A.; Ebert, B. L. |
| Article Title: | SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia |
| Abstract: | Mutations in SETD2, encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia. We investigated the impact of SETD2 mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of Setd2. SETD2 mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non–DNA damaging agent, L-asparaginase. H3K36me3 localizes components of the DNA damage response (DDR) pathway and SETD2 mutation impaired DDR, blunting apoptosis induced by cytotoxic chemotherapy. Consistent with local recruitment of DDR, genomic regions with higher H3K36me3 had a lower mutation rate, which was increased with SETD2 mutation. Heterozygous conditional inactivation of Setd2 in a murine model decreased the latency of MLL-AF9–induced leukemia and caused resistance to cytarabine treatment in vivo, whereas homozygous loss delayed leukemia formation. Treatment with JIB-04, an inhibitor of the H3K9/36me3 demethylase KDM4A, restored H3K36me3 levels and sensitivity to cytarabine. These findings establish SETD2 alteration as a mechanism of resistance to DNA-damaging chemotherapy, consistent with a local loss of DDR, and identify a potential therapeutic strategy to target SETD2-mutant leukemias. © 2017 by The American Society of Hematology. |
| Keywords: | cancer survival; controlled study; unclassified drug; gene mutation; doxorubicin; cancer combination chemotherapy; drug potentiation; nonhuman; cytarabine; mouse; cell viability; dna damage; apoptosis; etoposide; animal experiment; animal model; protein; in vivo study; in vitro study; heterozygote; cancer resistance; acute leukemia; histone methyltransferase; histone h3; homozygote; asparaginase; dna damage response; pharmacogenetics; tioguanine; genomic dna; concentration response; leukemia cell line; knockout gene; antileukemic agent; setd2 protein; male; female; priority journal; article; murine leukemia; 2 allyl 1 [6 (1 hydroxy 1 methylethyl) 2 pyridinyl] 6 [4 (4 methyl 1 piperazinyl)anilino] 1h pyrazolo[3,4 d]pyrimidin 3(2h) one; histone 3 lysine 36 trimethyltransferase; jib 04 |
| Journal Title: | Blood |
| Volume: | 130 |
| Issue: | 24 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2017-12-14 |
| Start Page: | 2631 |
| End Page: | 2641 |
| Language: | English |
| DOI: | 10.1182/blood-2017-03-775569 |
| PROVIDER: | scopus |
| PMCID: | PMC5731084 |
| PUBMED: | 29018079 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
