Runx1-R188Q germ line mutation induces inflammation and predisposition to hematologic malignancies in mice.
Runx1-R188Q germ line mutation induces inflammation and predisposition to hematologic malignancies in mice.
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DOI：
10.1182/bloodadvances.2023010398
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发表时间：
2023-12-12
期刊：
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
作者：
种系Runx1突变解除了骨髓中炎症细胞因子的调节，易患血液恶性肿瘤。Runx1R188Q/+ lt - hsc在Runx1R188Q/+受体中具有竞争优势，这引起了人们对使用基因编辑纠正疗法的担忧。RUNX1基因的种系突变导致家族性血小板疾病（FPD），这是一种与造血恶性肿瘤（HM）终生风险相关的遗传性疾病。FPD患者在HM发病前经常表现为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，但其在恶性前骨髓（BM）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室。免疫表型分析显示Runx1R188Q/+小鼠造血干细胞和祖细胞（HSPCs）数量增加。然而，Sca-1和CD86标志物的比较表明，Sca-1的表达可能是全身性炎症的结果。细胞因子分析证实了BM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在Runx1R188Q/+ HSPCs中的表达也有所增加。体外实验中，Runx1R188Q/+造血祖细胞dna损伤应答活性存在缺陷，提示Runx1R188Q可能促进基因组不稳定性。Runx1R188Q/+受体小鼠的长期再生造血干细胞分化减少。此外，我们发现Runx1R188Q/+ HSPCs在双向再种群分析中优于野生型HSPCs，并且在这种设置下，受体小鼠的遗传组成对克隆动力学没有显著影响。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一起易患HM。这些研究建立了一种新的小鼠FPDHM模型，并证明生殖系Runx1突变诱导了一种以BM炎症、选择性扩张能力、有缺陷的dna损伤反应和HM易感性为特征的癌前表型。
Germ line Runx1 mutations deregulate inflammatory cytokines in bone marrow and predispose to hematologic malignancies. Runx1R188Q/+ LT-HSCs have competitive advantage in Runx1R188Q/+ recipients, raising concerns on the use of gene-editing corrective therapies. 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.
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