Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia.
Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia.
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DOI：
10.1016/j.cancergen.2015.01.007
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发表时间：
2015-04
期刊：
影响因子：
1.9
通讯作者：
Bessler M
中科院分区：
文献类型：
--
作者：
Babushok DV;Perdigones N;Perin JC;Olson TS;Ye W;Roth JJ;Lind C;Cattier C;Li Y;Hartung H;Paessler ME;Frank DM;Xie HM;Cross S;Cockroft JD;Podsakoff GM;Monos D;Biegel JA;Mason PJ;Bessler M
获得性再生障碍性贫血（aAA）是一种由自身免疫破坏早期造血细胞引起的非恶性疾病。克隆性造血是一种晚期并发症，见于20-25%的老年患者。我们假设aAA中的克隆造血是一种更普遍的现象，即使在年轻患者中也可以在疾病早期出现。为了评估aAA的克隆造血，我们对22例患者的配对骨髓和皮肤进行了比较性全外显子组测序。我们在16例患者（72.7%）中发现了体细胞突变，中位病程为1年; 12例（66.7%）为儿童型aAA患者。51个独特基因中的58个突变主要发生在免疫和转录调控途径中。最常见的突变是PIGA，有7个突变。在MDS中，只有两个突变发生在复发突变的基因中。两名患者有HLA等位基因的寡克隆丢失，将免疫逃逸与克隆出现联系起来。2例患者在关键信号传导途径中存在激活突变（STAT 5 B（p.N642H）、CAMK 2G（p.T306M））。我们的研究结果表明，aAA中的克隆性造血是常见的，有两种机制出现-免疫逃逸和增殖增加。我们的发现扩展了对这种非肿瘤性血液疾病的概念性理解。未来对aAA患者克隆造血的前瞻性研究对于理解结局和设计个性化治疗策略至关重要。
Acquired aplastic anemia (aAA) is a non-malignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20–25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin in 22 patients. We found somatic mutations in sixteen patients (72.7%) with a median disease duration of 1 year; twelve (66.7%) were patients with pediatriconset aAA. Fifty-eight mutations in 51 unique genes were primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA, with 7 mutations. Only two mutations were in genes recurrently-mutated in MDS. Two patients had oligoclonal loss of HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B(p.N642H), CAMK2G(p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging― immune escape and increased proliferation. Our findings expand conceptual understanding of this non-neoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes, and for designing personalized treatment strategies.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
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：
--
作者：
Kubokawa M;Nakamura K;Komagiri Y
通讯作者：
Komagiri Y
影响因子：
7.8
作者：
Du, Hong-Yan;Idol, Rachel;Bessler, Monica
通讯作者：
Bessler, Monica
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y