Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Blood Adv. 2023 Dec 12;7(23):7304-7318. doi: 10.1182/bloodadvances.2023010398.
Germ line mutations in the RUNX1 gene cause familial platelet disorder (FPD), an inherited disease associated with lifetime risk to hematopoietic malignancies (HM). Patients with FPD frequently show clonal expansion of premalignant cells preceding HM onset. Despite the extensive studies on the role of RUNX1 in hematopoiesis, its function in the premalignant bone marrow (BM) 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 in the number 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 BM. 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, using 3 mouse models. These studies establish a novel murine FPDHM model and demonstrate that germ line Runx1 mutations induce a premalignant phenotype marked by BM inflammation, selective expansion capacity, defective DNA-damage response, and predisposition to HM.
RUNX1 基因中的种系突变导致家族性血小板疾病 (FPD)，这是一种与终生发生造血恶性肿瘤 (HM) 风险相关的遗传性疾病。FPD 患者在 HM 发病前常表现出恶性前细胞的克隆性扩张。尽管对 RUNX1 在造血中的作用进行了广泛的研究，但它在恶性前骨髓 (BM) 中的功能尚未得到很好的理解。在这里，我们使用携带 FPD 相关突变的 Runx1R188Q 小鼠品系来描述造血祖细胞区室。免疫表型分析显示，Runx1R188Q/+ 小鼠的造血干细胞和祖细胞 (HSPC) 数量增加。然而，Sca-1 和 CD86 标志物的比较表明，Sca-1 的表达可能是由全身炎症引起的。细胞因子谱分析证实 BM 中干扰素反应细胞因子失调。此外，另一种炎症反应蛋白 CD48 的表达也在 Runx1R188Q/+ HSPC 中增加。Runx1R188Q/+ 造血祖细胞的 DNA 损伤反应活性在体外有缺陷，表明 Runx1R188Q 可能促进基因组不稳定。Runx1R188Q/+ 受体小鼠中的长期重编程 HSC 分化减少。此外，我们发现 Runx1R188Q/+ HSPC 在双向重编程实验中与野生型 HSPC 竞争，并且在这种情况下，受体小鼠的遗传构成并没有显著影响克隆动力学。最后，我们使用 3 种小鼠模型证明，Runx1R188Q 与 FPDHM 中发现的体细胞突变协同作用，导致 HM。这些研究建立了一种新的小鼠 FPDHM 模型，并证明种系 RUNX1 突变诱导以 BM 炎症、选择性扩增能力、DNA 损伤反应缺陷和 HM 易感性为特征的恶性前表型。
