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 7

Foxm1 haploinsufficiency promotes AML1-ETO9a–induced MPN/AML in mice.

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Foxm1 haploinsufficiency promotes AML1-ETO9a–induced MPN/AML in mice. (...
(A) Comparison of expression levels in patients with t(8;21) AML (ref. 66) (n = 40) and healthy individuals from the control group (n = 74) using data derived from GSE13159. (B) Kaplan-Meier survival analysis of EV-Foxm1 HET mice (n = 7), WT AML1-ETO9a (AE9a) mice (n = 9), and AE9a-Foxm1 HET mice (n = 8). Log-rank test. The double-headed arrow denotes the difference (P value) between two groups as indicated. (C) The frequency of GFP+ cells in BM and spleen. (D and E) The frequency of GFP+ myeloid cells (D) and GFP+ red blood cells (E) in BM cells and splenic cells. n = 6 for WT AE9a group, n = 4 for AE9a-Foxm1 HET group. (F) Flow cytometric analysis of the percentage of Lin– cells and GFP+Lin–c-Kit+ cells in BM. (G) Quantification of the percentage of GFP+Lin–c-Kit+ cells. n = 6 for WT AE9a mice, n = 4 for AE9a-Foxm1 HET mice. (H) Wright-Giemsa–stained BM cells and H&E-stained spleen, liver, and lung from WT AE9a and AE9a-Foxm1 HET mice. Data are presented as mean ± SD. *P <0.05, **P < 0.01, ****P < 0.0001; 2-tailed Student’s t test, or log-rank (Mantel-Cox) test for survival curve. Scale bar: 20 μm (BM); 1 mm (spleen); 200 μm (spleen inset); 100 μm (liver and lung).