Foxm1 haploinsufficiency drives clonal hematopoiesis and promotes a stress-related transition to hematologic malignancy in mice
Chunjie Yu, Yue Sheng, Fang Yu, Hongyu Ni, Alan Qiu, Yong Huang, Zhijian Qian
Chunjie Yu, Yue Sheng, Fang Yu, Hongyu Ni, Alan Qiu, Yong Huang, Zhijian Qian
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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 5

Foxm1 haploinsufficiency results in a defect in DNA damage repair in HSPCs.

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Foxm1 haploinsufficiency results in a defect in DNA damage repair in HS...
(A) Representative flow cytometric plots show the percentage of γH2AX+ cells in LSK and HSC populations from Tie2-Cre Foxm1fl/+ mice (n = 3) and control mice (n = 3) 24 hours after LPS injection. (B) Histogram shows the percentage of γH2AX+ cells in LSK and HSC populations. (C) Representative images of γH2AX foci in Lin–c-Kit+ BM cells isolated from Tie2-Cre Foxm1fl/+ and control mice after LPS injection. Magnification: ×63 oil for C and ×20 for F. (D) Quantification of the number of cells with more 5 γH2AX foci per 100 Lin–c-Kit+ BM cells from the mice injected with LPS after 24 hours. n = 3 for each group. (E) Quantification of the mean γH2AX foci/cells in Lin–c-Kit+ BM cells from the mice injected with LPS after 24 hours. n = 3 for each group. (F) Representative images of the alkaline comet assay detecting DNA damage in Lin–c-Kit+ BM cells from mice injected with LPS after 24 hours. (G) Quantitative results of the tail olive moment for the alkaline comet assay. Three independent experiments were performed, and the results presented are the pooled data from all 3 experiments. (H) Quantification of the number of cells with more 5 γH2AX foci per 100 Lin– BM cells exposed to irradiation (0.5 Gy) at different time points. n = 3 for each group. (I) Quantification of the mean γH2AX foci/cell in Lin– BM cells exposed to irradiation (0.5 Gy) at different time points. n = 3 for each group. (J–M) Kinetics of γH2AX+ cells in different populations from the cells exposed to 0.5 Gy irradiation over the indicated period. n = 3 for each group. Data are representative of at least 2 independent experiments and expressed as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001; 2-tailed Student’s t test.