由染色体1q/MDM4三倍体驱动的克隆性造血，定义了范可尼贫血中发展白血病的典型途径。
Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia.
发表日期：2023 Feb 02
作者：
Marie Sebert, Stéphanie Gachet, Thierry Leblanc, Alix Rousseau, Olivier Bluteau, Rathana Kim, Raouf Ben Abdelali, Flore Sicre de Fontbrune, Loïc Maillard, Carèle Fedronie, Valentine Murigneux, Léa Bellenger, Naira Naouar, Samuel Quentin, Lucie Hernandez, Nadia Vasquez, Mélanie Da Costa, Pedro H Prata, Lise Larcher, Marie de Tersant, Matthieu Duchmann, Anna Raimbault, Franck Trimoreau, Odile Fenneteau, Wendy Cuccuini, Nathalie Gachard, Nathalie Auger, Giulia Tueur, Maud Blanluet, Claude Gazin, Michèle Souyri, Francina Langa Vives, Aaron Mendez-Bermudez, Hélène Lapillonne, Etienne Lengline, Emmanuel Raffoux, Pierre Fenaux, Lionel Adès, Edouard Forcade, Charlotte Jubert, Carine Domenech, Marion Strullu, Bénédicte Bruno, Nimrod Buchbinder, Caroline Thomas, Arnaud Petit, Guy Leverger, Gérard Michel, Marina Cavazzana, Eliane Gluckman, Yves Bertrand, Nicolas Boissel, André Baruchel, Jean-Hugues Dalle, Emmanuelle Clappier, Eric Gilson, Ludovic Deriano, Sylvie Chevret, François Sigaux, Gérard Socié, Dominique Stoppa-Lyonnet, Hugues de Thé, Christophe Antoniewski, Dominique Bluteau, Régis Peffault de Latour, Jean Soulier
来源：
Cell Stem Cell
摘要：
Fanconi贫血（FA）患者经历染色体不稳定，导致造血干/祖细胞（HSPC）枯竭和易发生预后差的髓系白血病。基于335名患者的纵向队列，我们对62名具有克隆进化的患者进行了临床、基因组和功能研究。我们发现一种独特的体细胞结构变异和突变模式，其中FA标志的是不平衡的微缩同源介导的易位驱动拷贝数变化，与BRCA相关癌症共享特征。其中一半的患者出现了染色体1q增益，并通过MDM4三倍体下调p53信号驱动克隆造血，随后发生二次急性髓系白血病基因改变。功能上，MDM4三倍体使小鼠和人类原发性FA HSPCs具有更高的适应性，挽救了炎症介导的骨髓衰竭，并在FA小鼠模型中驱动克隆优势，而靶向MDM4在体内外干扰了白血病细胞。我们的研究结果识别了朝向二次白血病发生的线性路径，并揭示了早期MDM4驱动的基础p53活化下调在其中发挥了关键作用，为监测和治疗方案开辟了新的前景。 版权所有©2023 Elsevier Inc. 发布。
Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitro and in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.Copyright © 2023. Published by Elsevier Inc.