Hematopoietic Cell Autonomous Disruption of Hematopoiesis in a Germline Loss-of-function Mouse Model of RUNX1-FPD.
Hematopoietic Cell Autonomous Disruption of Hematopoiesis in a Germline Loss-of-function Mouse Model of RUNX1-FPD.
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DOI：
10.1097/hs9.0000000000000824
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发表时间：
2023-02
期刊：
影响因子：
6.6
通讯作者：
Raaijmakers, Marc H. G. P.
中科院分区：
文献类型：
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作者：
Ernst, Martijn P. T.;Pronk, Eline;van Dijk, Claire;van Strien, Paulina M. H.;van Tienhoven, Tim V. D.;Wevers, Michiel J. W.;Sanders, Mathijs A.;Bindels, Eric M. J.;Speck, Nancy A.;Raaijmakers, Marc H. G. P.
RUNX1家族性血小板紊乱(RUNX1-FPD)是一种由RUNX1基因种系功能丧失突变引起的造血系统疾病，其特征是血小板减少、血小板减少和发展为血液系统恶性肿瘤的风险增加，主要是髓系来源。疾病的病理生理学仍不完全清楚，部分原因是缺乏体内模型来概括在人类中发现的生殖系RUNX1功能丧失，从而排除了非造血细胞在疾病发病机制中的潜在贡献的研究。在这里，我们研究了携带一个RUNX1等位基因的胚系亚型突变和另一个RUNX1等位基因功能丧失突变的小鼠(Runx1L148A/−小鼠)，这些小鼠表现出许多在人类RUNX1-FPD患者中发现的血液学特征。Runx1L148A/−小鼠表现出强烈而显著的血小板减少和髓系偏向造血，与造血干细胞固有的重建缺陷和髓系祖细胞库的扩大有关。我们证明了在Prrx1-cre中RUNX1从骨髓基质细胞中的特异性缺失；Runx1fl/fl小鼠没有概括这些异常，表明造血异常是造血谱系固有的，并反对骨髓微环境的驱动作用。总之，我们报告了一种RUNX1-FPD小鼠模型，忠实地概括了人类疾病的关键特征。研究结果不支持辅助的、非造血细胞在体内平衡条件下破坏造血的驱动作用。
RUNX1 familial platelet disorder (RUNX1-FPD) is a hematopoietic disorder caused by germline loss-of-function mutations in the RUNX1 gene and characterized by thrombocytopathy, thrombocytopenia, and an increased risk of developing hematologic malignancies, mostly of myeloid origin. Disease pathophysiology has remained incompletely understood, in part because of a shortage of in vivo models recapitulating the germline RUNX1 loss of function found in humans, precluding the study of potential contributions of non-hematopoietic cells to disease pathogenesis. Here, we studied mice harboring a germline hypomorphic mutation of one Runx1 allele with a loss-of-function mutation in the other Runx1 allele (Runx1L148A/− mice), which display many hematologic characteristics found in human RUNX1-FPD patients. Runx1L148A/− mice displayed robust and pronounced thrombocytopenia and myeloid-biased hematopoiesis, associated with an HSC intrinsic reconstitution defect in lymphopoiesis and expansion of myeloid progenitor cell pools. We demonstrate that specific deletion of Runx1 from bone marrow stromal cells in Prrx1-cre;Runx1fl/fl mice did not recapitulate these abnormalities, indicating that the hematopoietic abnormalities are intrinsic to the hematopoietic lineage, and arguing against a driving role of the bone marrow microenvironment. In conclusion, we report a RUNX1-FPD mouse model faithfully recapitulating key characteristics of human disease. Findings do not support a driving role of ancillary, non-hematopoietic cells in the disruption of hematopoiesis under homeostatic conditions.
影响因子：
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作者：
Schmit, Jessica M;Turner, Daniel J;Hromas, Robert A;Wingard, John R;Brown, Randy A;Li, Ying;Li, Marilyn M;Slayton, William B;Cogle, Christopher R
通讯作者：
Cogle, Christopher R