Format

Send to

Choose Destination
Blood. 2017 Dec 14;130(24):2631-2641. doi: 10.1182/blood-2017-03-775569. Epub 2017 Oct 10.

SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
2
Division of Hematology, Brigham and Women's Hospital, Boston, MA.
3
Netherlands Cancer Institute, Amsterdam, The Netherlands.
4
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY; and.
5
Oncology Division, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO.

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.

PMID:
29018079
PMCID:
PMC5731084
DOI:
10.1182/blood-2017-03-775569
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center