Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.
Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA.
J Clin Invest. 2023 Aug 1;133(15):e163911. doi: 10.1172/JCI163911.
Clonal hematopoiesis plays a critical role in the initiation and development of hematologic malignancies. In patients with del(5q) myelodysplastic syndrome (MDS), the transcription factor FOXM1 is frequently downregulated in CD34+ cells. In this study, we demonstrated that Foxm1 haploinsufficiency disturbed normal hematopoiesis and conferred a competitive repopulation advantage for a short period. However, it impaired the long-term self-renewal capacity of hematopoietic stem cells, recapitulating the phenotypes of abnormal hematopoietic stem cells observed in patients with MDS. Moreover, heterozygous inactivation of Foxm1 led to an increase in DNA damage in hematopoietic stem/progenitor cells (HSPCs). Foxm1 haploinsufficiency induced hematopoietic dysplasia in a mouse model with LPS-induced chronic inflammation and accelerated AML-ETO9a-mediated leukemogenesis. We have also identified Parp1, an important enzyme that responds to various types of DNA damage, as a target of Foxm1. Foxm1 haploinsufficiency decreased the ability of HSPCs to efficiently repair DNA damage by downregulating Parp1 expression. Our findings suggest that the downregulation of the Foxm1-Parp1 molecular axis may promote clonal hematopoiesis and reduce genome stability, contributing to del(5q) MDS pathogenesis.
克隆性造血在血液系统恶性肿瘤的发生和发展中起着关键作用。在 del(5q) 骨髓增生异常综合征（MDS）患者中，转录因子 FOXM1 在 CD34+细胞中经常下调。在这项研究中，我们证明了 Foxm1 杂合性不足扰乱了正常造血，并在短时间内赋予了竞争性再群体优势。然而，它损害了造血干细胞的长期自我更新能力，再现了 MDS 患者中观察到的异常造血干细胞表型。此外，Foxm1 的杂合失活导致造血干细胞/祖细胞（HSPC）中的 DNA 损伤增加。Foxm1 杂合性不足导致 LPS 诱导的慢性炎症小鼠模型中的造血发育不良，并加速了 AML-ETO9a 介导的白血病发生。我们还确定了 Parp1，一种对各种类型的 DNA 损伤做出反应的重要酶，是 Foxm1 的靶标。Foxm1 杂合性不足通过下调 Parp1 表达降低了 HSPC 有效修复 DNA 损伤的能力。我们的研究结果表明，Foxm1-Parp1 分子轴的下调可能促进克隆性造血并降低基因组稳定性，导致 del(5q) MDS 的发病机制。
