Mar Brenton G, Chu S Haihua, Kahn Josephine D, Krivtsov Andrei V, Koche Richard, Castellano Cecilia A, Kotlier Jacob L, Zon Rebecca L, McConkey Marie E, Chabon Jonathan, Chappell Ryan, Grauman Peter V, Hsieh James J, Armstrong Scott A, Ebert Benjamin L
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
Division of Hematology, Brigham and Women's Hospital, Boston, MA.
Blood. 2017 Dec 14;130(24):2631-2641. doi: 10.1182/blood-2017-03-775569. Epub 2017 Oct 10.
Mutations in encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia. We investigated the impact of mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of 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 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 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 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 -mutant leukemias.
编码组蛋白3赖氨酸36三甲基转移酶的SETD2突变在复发的急性淋巴细胞白血病和MLL重排的急性白血病中富集。我们研究了SETD2突变对同基因白血病细胞系以及由条件性敲除产生的小鼠白血病化疗敏感性的影响。SETD2突变导致对DNA损伤剂、阿糖胞苷、6-硫鸟嘌呤、多柔比星和依托泊苷耐药，但对非DNA损伤剂L-天冬酰胺酶不耐药。H3K36me3定位DNA损伤反应（DDR）途径的成分，SETD2突变损害DDR，减弱细胞毒性化疗诱导的细胞凋亡。与DDR的局部募集一致，H3K36me3水平较高的基因组区域突变率较低，而SETD2突变会使其增加。在小鼠模型中SETD2的杂合条件性失活降低了MLL-AF9诱导的白血病的潜伏期，并导致体内对阿糖胞苷治疗耐药，而纯合缺失则延迟白血病形成。用H3K9/36me3去甲基化酶KDM4A的抑制剂JIB-04处理可恢复H3K36me3水平和对阿糖胞苷的敏感性。这些发现确定SETD2改变是对DNA损伤化疗耐药的一种机制，与DDR的局部丧失一致，并确定了一种针对SETD2突变白血病的潜在治疗策略。
