RUNX1 基因的种系突变会导致家族性血小板疾病 (FPD)，这是一种与终生造血系统恶性肿瘤 (HM) 风险相关的遗传性疾病。 FPD 患者在 HM 发病前经常表现出癌前细胞的克隆扩增。尽管对 RUNX1 在造血中的作用进行了广泛的研究，但其在癌前骨髓中的功能尚不清楚。在这里，我们使用携带 FPD 相关突变 Runx1R188Q 的小鼠品系来表征造血祖细胞区室。免疫表型分析显示 Runx1R188Q/ 小鼠的造血干细胞和祖细胞 (HSPC) 有所增加。然而，Sca-1和CD86标记物的比较表明Sca-1表达可能是由全身炎症引起的。细胞因子分析证实了骨髓中干扰素反应细胞因子的失调。此外，另一种炎症反应蛋白CD48的表达在Runx1R188Q/HSPC中也增加。 Runx1R188Q/造血祖细胞的DNA损伤反应活性在体外存在缺陷，表明Runx1R188Q可能促进基因组不稳定。 Runx1R188Q/受体小鼠中长期重新增殖的HSC的分化减少。此外，我们发现 Runx1R188Q/HSPC 在双向再增殖测定中胜过野生型对应物，并且受体小鼠的基因构成在此设置下并未显着影响克隆动态。最后，我们利用三种小鼠模型证明了 Runx1R188Q 与 FPDHM 中发现的体细胞突变共同导致 HM。这些研究建立了一种新型小鼠 FPDHM 模型，并证明种系 Runx1 突变会诱导恶性前表型，其特征是骨髓炎症、选择性扩张能力、DNA 损伤反应缺陷和 HM 易感性。版权所有 © 2023 美国血液学会。

Germline mutations in the RUNX1 gene cause familial platelet disorder (FPD), an inherited disease associated with lifetime risk to hematopoietic malignancies (HM). FPD patients frequently show clonal expansion of pre-malignant cells preceding HM onset. Despite the extensive studies on the role of RUNX1 in hematopoiesis, its function in the pre-malignant bone marrow is not well understood. Here, we characterized the hematopoietic progenitor compartments using a mouse strain carrying an FPD-associated mutation, Runx1R188Q. Immunophenotypic analysis showed an increase of hematopoietic stem and progenitor cells (HSPCs) in the Runx1R188Q/+ mice. However, the comparison of Sca-1 and CD86 markers suggested that Sca-1 expression may result from systemic inflammation. Cytokine profiling confirmed the dysregulation of interferon-response cytokines in the bone marrow. Furthermore, the expression of CD48, another inflammation response protein, was also increased in Runx1R188Q/+ HSPCs. The DNA-damage response activity of Runx1R188Q/+ hematopoietic progenitor cells was defective in vitro, suggesting that Runx1R188Q may promote genomic instability. The differentiation of long-term repopulating HSCs was reduced in Runx1R188Q/+ recipient mice. Furthermore, we found that Runx1R188Q/+ HSPCs outcompete their wild type counterparts in bidirectional repopulation assays, and that the genetic makeup of recipient mice did not significantly affect the clonal dynamics under this setting. Finally, we demonstrate that Runx1R188Q predisposes to HM in cooperation with somatic mutations found in FPDHM, utilizing three mouse models. These studies establish a novel murine FPDHM model and demonstrate that germline Runx1 mutations induce a pre-malignant phenotype marked by bone marrow inflammation, selective expansion capacity, defective DNA-damage response, and predisposition to HM.Copyright © 2023 American Society of Hematology.