DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling.
DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling.
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DOI：
10.1038/nm.4210
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发表时间：
2016-12
期刊：
影响因子：
82.9
通讯作者：
Levine RL
中科院分区：
文献类型：
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作者：
Guryanova OA;Shank K;Spitzer B;Luciani L;Koche RP;Garrett-Bakelman FE;Ganzel C;Durham BH;Mohanty A;Hoermann G;Rivera SA;Chramiec AG;Pronier E;Bastian L;Keller MD;Tovbin D;Loizou E;Weinstein AR;Gonzalez AR;Lieu YK;Rowe JM;Pastore F;McKenney AS;Krivtsov AV;Sperr WR;Cross JR;Mason CE;Tallman MS;Arcila ME;Abdel-Wahab O;Armstrong SA;Kubicek S;Staber PB;Gönen M;Paietta EM;Melnick AM;Nimer SD;Mukherjee S;Levine RL
虽然大多数急性髓性白血病（AML）患者最初对化疗有反应，但许多患者随后复发;化疗后AML持续存在的机制基础尚未阐明。DNA甲基转移酶3A（DNMT 3A）的复发性体细胞突变，最常见于精氨酸882（DNMT 3Amut），见于AML和无白血病转化的克隆性造血个体。DNMT 3Amut AML患者在接受标准剂量的柔红霉素诱导化疗时结局较差，这表明DNMT 3Amut细胞持续存在并促使复发。在这里，我们表明Dnmt 3amut诱导造血干细胞（HSC）扩增，与Flt 3 ITD和Npm 1c合作在体内诱导AML，并促进对蒽环类化疗的耐药性。在AML患者中，DNMT 3AR 882突变预测微小残留病（MRD），强调了它们在AML化疗耐药性中的作用。DNMT 3Amut细胞显示受损的核小体驱逐和染色质重塑响应于蒽环类药物，这是由于蒽环类药物暴露后组蛋白伴侣SPT-16的募集减弱所致。这种缺陷导致不能感知和修复DNA扭转应力，这导致增加的诱变。我们的研究确定了DNMT 3AR 882突变在驱动AML化疗耐药性中的关键作用，并强调了染色质重塑在细胞毒性化疗中的重要性。
Although the majority of acute myeloid leukemia (AML) patients initially respond to chemotherapy, many patients subsequently relapse; the mechanistic basis for AML persistence following chemotherapy has not been delineated. Recurrent somatic mutations in DNA methyltransferase 3A (DNMT3A), most frequently at arginine 882 (DNMT3Amut), are observed in AML and in individuals with clonal hematopoiesis in the absence of leukemic transformation. DNMT3Amut AML patients have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3Amut cells persist and drive relapse. Here we show that Dnmt3amut induces hematopoietic stem cell (HSC) expansion, cooperates with Flt3ITD and Npm1c to induce AML in vivo, and promotes resistance to anthracycline chemotherapy. In AML patients, DNMT3AR882 mutations predict for minimal residual disease (MRD), underscoring their role in AML chemoresistance. DNMT3Amut cells show impaired nucleosome eviction and chromatin remodeling in response to anthracyclines, resulting from attenuated recruitment of histone chaperone SPT-16 following anthracycline exposure. This defect leads to an inability to sense and repair DNA torsional stress, which results in increased mutagenesis. Our studies identify a critical role for DNMT3AR882 mutations in driving AML chemoresistance, and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.