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Foxm1 haploinsufficiency drives clonal hematopoiesis in vivo and promotes the transition to hematologic malignancy under stress

ABSTRACT: Clonal hematopoiesis plays a critical role in the initiation and development of hematologic malignant diseases. FOXM1, a well-known transcription factor, is often downregulated in CD34+ cells from patients with del(5q) Myelodysplastic Syndrome (MDS). Here we show that Foxm1 haploinsufficiency disturbs normal hematopoiesis and confers a competitive repopulation advantage to hematopoietic stem cells (HSCs) for a short period, but disrupts the long-term self-renewal capacity of HSCs, recapitulating the phenotypes of abnormal HSCs in MDS patients. Moreover, heterozygous inactivation of Foxm1 leads to an increase in DNA damage in hematopoietic stem/progenitor cells (HSPCs). Foxm1 haploinsufficiency induces an MDS-like disease in a mouse model with LPS-induced chronic inflammation, and accelerates AML-ETO9a-mediated leukemogenesis. We also identified PARP1, an important enzyme responding to various kinds of DNA lesions, as a previously unrecognized target of Foxm1. Foxm1 haploinsufficiency inhibits DNA damage response (DDR) in HSCs by downregulating PARP1 expression in HSPCs. Given that PARP1 inhibitors increase the risk of MDS and AML in clinical therapy for solid tumors, our results suggest that downregulation of the Foxm1-PARP1 molecular axis plays a pivotal role in the pathogenesis of MDS by promoting clonal hematopoiesis and reducing genome stability.

ORGANISM(S): Mus musculus

PROVIDER: GSE208564 | GEO | 2022/08/10

REPOSITORIES: GEO

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