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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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 1

Foxm1 haploinsufficiency promotes the expansion of HSCs by pushing HSC exit from quiescence.

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Foxm1 haploinsufficiency promotes the expansion of HSCs by pushing HSC ...
(A) Flow cytometric analysis of HPC, LSK, HSC, granulocyte-monocyte progenitor (GMP), common myeloid progenitor (CMP), and megakaryocyte-erythrocyte progenitor (MEP) populations in BM cells from Foxm1fl/+ mice or Tie2-Cre Foxm1fl/+ mice. (B) A total number of LSK cells and HSCs in BM from 8-week-old Foxm1fl/+ mice (n =3) and Tie2-Cre Foxm1fl/+ mice (n = 3). (C) Total number of HPC, GMP, CMP, and MEP cells in BM from 8-week-old Foxm1fl/+ mice (n = 3) or Tie2-Cre Foxm1fl/+ mice (n = 3). (D and E) Cell cycle analysis using DAPI (DNA content) and Ki-67 (proliferative cells) staining in HSCs, as determined by FACS. n = 5 mice for each group. (F and G) Cell cycle analysis using Hoechst (DNA dye) and Pyronin Y (RNA dye) staining in HSCs, as determined by FACS. n =4 mice for each group. (H and I) Cell cycle analysis using DAPI (DNA content) and BrdU (cells in S phase) staining in HSCs, as determined by FACS. n =3 mice for each group. (J) Kaplan-Meier survival curve of Foxm1fl/+ (n = 20) and Mx1-Cre Foxm1fl/+ mice (n = 19) after multiple injections (upward arrows) of 5-FU (150 mg/kg body weight). The double-headed arrow denotes the difference (P value) between two groups as indicated. Log-rank (Mantel-Cox) test. (K) The colony-forming assay shows repopulation ability. 5 × 104 cell input for the first round, and 1.5 × 105 cell input for the second round and third rounds. 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 or log-rank (Mantel-Cox) test for survival curve.