PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.
PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.
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DOI：
10.1016/j.stem.2018.10.004
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发表时间：
2018-11-01
期刊：
影响因子：
23.9
通讯作者：
Goodell MA
中科院分区：
文献类型：
--
作者：
Hsu JI;Dayaram T;Tovy A;De Braekeleer E;Jeong M;Wang F;Zhang J;Heffernan TP;Gera S;Kovacs JJ;Marszalek JR;Bristow C;Yan Y;Garcia-Manero G;Kantarjian H;Vassiliou G;Futreal PA;Donehower LA;Takahashi K;Goodell MA
克隆造血（CH）是干细胞克隆主导血液生成，随着年龄的增长变得越来越普遍，并可能预示着恶性肿瘤的发展。促进特定克隆优势的条件尚不清楚。我们发现 PPM1D（蛋白磷酸酶 Mn2+/Mg2+ 依赖性 1D）突变是一种 DNA 损伤反应调节因子，在 CH 中经常发生突变，五分之一的治疗相关急性髓性白血病或骨髓增生异常综合征患者中存在突变，并且与顺铂暴露密切相关。具有高活性 PPM1D 突变的细胞系在暴露于包括顺铂在内的细胞毒性 DNA 损伤剂后会扩张，从而在竞争中胜过正常细胞，这种效应主要是通过增加对细胞凋亡的抵抗力来介导的。此外，在暴露于顺铂和阿霉素后，杂合突变型 Ppm1d 造血细胞在体内竞争中胜过野生型造血细胞，但在骨髓移植恢复期间却没有。这些发现确立了 CH 中 PPM1D 突变的临床相关性以及研究突变与治疗相互作用的重要性。约 20% 患有治疗相关 AML 或 MDS 的患者出现 PPM1D 突变。 PPM1D 突变与之前接触特定 DNA 损伤剂有关。 突变型 PPM1D 在顺铂诱导的应激后具有生存优势。 PPM1D 突变体在骨髓移植应激下缺乏优势。 细胞毒性化疗使患者面临未来发生造血系统恶性肿瘤的风险。 Goodell 及其同事表明，PPM1D 突变使造血克隆能够抵抗顺铂等 DNA 损伤剂，从而赋予它们生存优势。选择压力针对不同的突变，在选择化疗时应予以考虑。
Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions. PPM1D is mutated in ∼20% of patients with therapy-related AML or MDS PPM1D mutations are associated with prior exposure to specific DNA-damaging agents Mutant PPM1D confers a survival advantage after cisplatin-induced stress PPM1D mutants lack an advantage under bone marrow transplantation stress Cytotoxic chemotherapies put patients at risk for future hematopoietic malignancies. Goodell and colleagues show that PPM1D mutations confer a survival advantage onto hematopoietic clones by rendering them resistant to DNA-damaging agents such as cisplatin. Selective pressures will be specific to different mutations and should be considered in choice of chemotherapy.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
8.8
作者：
Gundry MC;Brunetti L;Lin A;Mayle AE;Kitano A;Wagner D;Hsu JI;Hoegenauer KA;Rooney CM;Goodell MA;Nakada D
通讯作者：
Nakada D
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1016/s1470-2045(16)30627-1
发表时间：
2017-01
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Gillis NK;Ball M;Zhang Q;Ma Z;Zhao Y;Yoder SJ;Balasis ME;Mesa TE;Sallman DA;Lancet JE;Komrokji RS;List AF;McLeod HL;Alsina M;Baz R;Shain KH;Rollison DE;Padron E
通讯作者：
Padron E
DOI：
10.1073/pnas.94.12.6048
发表时间：
1997-06-10
影响因子：
11.1
作者：
Fiscella, M;Zhang, HL;Appella, E
通讯作者：
Appella, E