Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
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DOI：
10.1038/s41467-021-21588-4
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发表时间：
2021-02-26
影响因子：
16.6
通讯作者：
Lindsley RC
中科院分区：
文献类型：
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作者：
Kennedy AL;Myers KC;Bowman J;Gibson CJ;Camarda ND;Furutani E;Muscato GM;Klein RH;Ballotti K;Liu S;Harris CE;Galvin A;Malsch M;Dale D;Gansner JM;Nakano TA;Bertuch A;Vlachos A;Lipton JM;Castillo P;Connelly J;Churpek J;Edwards JR;Hijiya N;Ho RH;Hofmann I;Huang JN;Keel S;Lamble A;Lau BW;Norkin M;Stieglitz E;Stock W;Walkovich K;Boettcher S;Brendel C;Fleming MD;Davies SM;Weller EA;Bahl C;Carter SL;Shimamura A;Lindsley RC
为了了解介导生殖系遗传性白血病易感性的机制，我们研究了遗传性核糖体病Shwachman-Diamond综合征（SDS），这是一种早期骨髓衰竭疾病，具有骨髓恶性肿瘤的高风险。为了明确SDS中克隆性造血的机制基础，我们研究了SDS患者获得的体细胞突变。在这里，我们报告了多个独立的体细胞造血克隆出现在生命早期，最常见的是EIF 6或TP 53的杂合突变。我们发现，生殖系SBDS缺陷建立了一个健身约束，驱动选择体细胞克隆通过两种不同的机制，具有不同的临床后果。EIF 6失活通过改善基础SDS核糖体缺陷和增强克隆适应性介导具有有限白血病潜能的代偿途径。TP 53突变通过灭活肿瘤抑制检查点而不纠正核糖体缺陷来定义具有增强的白血病潜能的适应不良途径。白血病的后续发展与双等位基因TP 53改变的获得相关。这些结果从机制上将白血病易感性与细胞适应性的生殖系遗传约束联系起来，并为临床监测策略提供了合理的框架。了解白血病易感性的分子基础对于干预至关重要。作者在此通过研究Shwachman-Diamond综合征来调查生殖系遗传性白血病易感性，并报告了EIF 6的补偿性失活突变和转化双等位基因TP 53的改变。
To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies. Understanding the molecular basis of leukaemia predisposition is essential for intervention. The authors here investigate germline genetic leukaemia predisposition by studying Shwachman-Diamond syndrome and report compensatory inactivating mutations in EIF6 and transforming biallelic TP53 alterations.
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影响因子：
82.9
作者：
Bernard E;Nannya Y;Hasserjian RP;Devlin SM;Tuechler H;Medina-Martinez JS;Yoshizato T;Shiozawa Y;Saiki R;Malcovati L;Levine MF;Arango JE;Zhou Y;Solé F;Cargo CA;Haase D;Creignou M;Germing U;Zhang Y;Gundem G;Sarian A;van de Loosdrecht AA;Jädersten M;Tobiasson M;Kosmider O;Follo MY;Thol F;Pinheiro RF;Santini V;Kotsianidis I;Boultwood J;Santos FPS;Schanz J;Kasahara S;Ishikawa T;Tsurumi H;Takaori-Kondo A;Kiguchi T;Polprasert C;Bennett JM;Klimek VM;Savona MR;Belickova M;Ganster C;Palomo L;Sanz G;Ades L;Della Porta MG;Elias HK;Smith AG;Werner Y;Patel M;Viale A;Vanness K;Neuberg DS;Stevenson KE;Menghrajani K;Bolton KL;Fenaux P;Pellagatti A;Platzbecker U;Heuser M;Valent P;Chiba S;Miyazaki Y;Finelli C;Voso MT;Shih LY;Fontenay M;Jansen JH;Cervera J;Atsuta Y;Gattermann N;Ebert BL;Bejar R;Greenberg PL;Cazzola M;Hellström-Lindberg E;Ogawa S;Papaemmanuil E
通讯作者：
Papaemmanuil E
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：
3.3
作者：
Barlow, Kyle A.;Conchuir, Shane O.;Kortemme, Tanja
通讯作者：
Kortemme, Tanja
影响因子：
20.3
作者：
Austin, KM;Leary, RJ;Shimamura, A
通讯作者：
Shimamura, A
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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