Journal
BLOOD
Volume 130, Issue 24, Pages 2631-2641Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-03-775569
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Funding
- William Lawrence and Blanche Hughes Foundation
- National Institutes of Health, National Cancer Institute [P01 CA066996, K08 CA184419]
- Leukemia and Lymphoma Society
- Howard Hughes Medical Institute
- St. Baldrick's Foundation Scholar grant
- Alex's Lemonade Stand Foundation Young Investigator grant
- Damon Runyon Cancer Research Foundation [DRSG-5-13]
- NWO Diamond Program
- Prins Bernard Cultural Fund
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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 SETD2mutations 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.
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