Foxm1 haploinsufficiency drives clonal hematopoiesis and promotes a stress-related transition to hematologic malignancy in mice
Chunjie Yu, … , Yong Huang, Zhijian Qian
Chunjie Yu, … , Yong Huang, Zhijian Qian
Published August 1, 2023
Citation Information: J Clin Invest. 2023;133(15):e163911. https://doi.org/10.1172/JCI163911.
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Research Article Hematology

Foxm1 haploinsufficiency drives clonal hematopoiesis and promotes a stress-related transition to hematologic malignancy in mice

Abstract

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.

Authors

Chunjie Yu, Yue Sheng, Fang Yu, Hongyu Ni, Alan Qiu, Yong Huang, Zhijian Qian

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Figure 4

Foxm1 regulates multiple signaling pathways in HSCs.

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Foxm1 regulates multiple signaling pathways in HSCs. (A) Heatmap of expr...
(A) Heatmap of expression profiles for genes with P < 0.05 (576 genes). (B) RT-PCR analysis shows the expression level of genes involved in stem cell functions and DNA damage repair pathway in HSCs from WT(n = 3) or Foxm1 HET(n = 3) mice. (C and D) GSEA plots show, respectively, a positive association with “KEGG Lysosome” and “GSE14769 UNSTIM VS 20MIN LPS BMDM UP” in Foxm1 HET HSCs compared with WT HSCs. (E and F) GSEA plots show a negative association with “HEME Metabolism” and “DNA Dependent DNA Replication Maintenance of Fidelity” in Foxm1 HET HSCs compared with WT HSCs. (G) Correlation between FOXM1 and PARP1 in MDS with deletion of chromosome 5q [del(5q) MDS] (n = 47). P value was calculated by Spearman’s r correlation. (H) Microarray analysis of PARP1 in CD34+ cells from individuals in the healthy control group (n =16) or from patients with del(5q) MDS (n = 43). (I) RT-PCR analysis of FOXM1 and PARP1 in MDSL cells transduced FOXM1 shRNAs and control vector; the results were normalized to ACTB expression. Data are presented as mean ± SD. *P < 0.05, **P < 0.01, 2-tailed Student’s t test.