SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints

Yunzhu Dong, Xinghui Zhao, Xiaomin Feng, Yile Zhou, Xiaomei Yan, Ya Zhang, Jiachen Bu, Di Zhan, Yoshihiro Hayashi, Yue Zhang, Zefeng Xu, Rui Huang, Jieyu Wang, Taoran Zhao, Zhijian Xiao, Zhenyu Ju, Paul R. Andreassen, Qian fei Wang, Wei Chen, Gang Huang

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

SETD2, an epigenetic tumor suppressor, is frequently mutated in MLL-rearranged (MLLr) leukemia and relapsed acute leukemia (AL). To clarify the impact of SETD2 mutations on chemotherapy sensitivity in MLLr leukemia, two loss-of-function (LOF) Setd2-mutant alleles (Setd2F2478L/WT or Setd2Ex6-KO/WT) were generated and introduced, respectively, to the Mll-Af9 knock-in leukemia mouse model. Both alleles cooperated with Mll-Af9 to accelerate leukemia development that resulted in resistance to standard Cytarabine-based chemotherapy. Mechanistically, Setd2-mutant leukemic cells showed downregulated signaling related to cell cycle progression, S, and G2/M checkpoint regulation. Thus, after Cytarabine treatment, Setd2-mutant leukemic cells exit from the S phase and progress to the G2/M phase. Importantly, S and G2/M cell cycle checkpoint inhibition could resensitize the Mll-Af9/Setd2 double-mutant cells to standard chemotherapy by causing DNA replication collapse, mitotic catastrophe, and increased cell death. These findings demonstrate that LOF SETD2 mutations confer chemoresistance on AL to DNA-damaging treatment by S and G2/M checkpoint defects. The combination of S and G2/M checkpoint inhibition with chemotherapy can be explored as a promising therapeutic strategy by exploiting their unique vulnerability and resensitizing chemoresistant AL with SETD2 or SETD2-like epigenetic mutations.

Original languageEnglish (US)
Pages (from-to)2585-2598
Number of pages14
JournalLeukemia
Volume33
Issue number11
DOIs
StatePublished - Nov 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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