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

Brenton G. Mar, S. Haihua Chu, Josephine D. Kahn, Andrei V. Krivstov, Richard Koche, Cecilia A. Castellano, Jacob L. Kotlier, Rebecca L. Zon, Marie E. McConkey, Jonathan Chabon, Ryan Chappell, Peter V. Grauman, James J. Hsieh, Scott A. Armstrong and Benjamin L. Ebert

Key points

  • Alterations of SETD2, a histone 3 lysine 36 trimethyl (H3K36me3) transferase leads to resistance to DNA damaging chemotherapy in leukemia.

  • Low H3K36me3 levels impair DNA damage response and increases mutation rate, which can be potentially targeted by H3K36me3 demethylase inhibition.

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 pathway and SETD2 mutation impaired the DNA damage response (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, while 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.

  • Submitted March 24, 2017.
  • Accepted September 18, 2017.