Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells
Qiong Wu, … , Jianxin Lyu, Zhijian Qian
Qiong Wu, … , Jianxin Lyu, Zhijian Qian
Published December 16, 2024
Citation Information: J Clin Invest. 2024;134(24):e173403. https://doi.org/10.1172/JCI173403.
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Research Article Hematology

Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells

Abstract

Ecotropic viral integration site 1 (EVI1/MECOM) is frequently upregulated in myeloid malignancies. Here, we present an Evi1-transgenic mouse model with inducible expression in hematopoietic stem/progenitor cells (HSPCs). Upon induction of Evi1 expression, mice displayed anemia, thrombocytopenia, lymphopenia, and erythroid and megakaryocyte dysplasia with a significant expansion of committed myeloid progenitor cells, resembling human myelodysplastic syndrome/myeloproliferative neoplasm–like (MDS/MPN–like) disease. Evi1 overexpression prompted HSPCs to exit quiescence and accelerated their proliferation, leading to expansion of committed myeloid progenitors while inhibiting lymphopoiesis. Analysis of global gene expression and Evi1 binding site profiling in HSPCs revealed that Evi1 directly upregulated lysine demethylase 6b (Kdm6b). Subsequently, Kdm6b-mediated H3K27me3 demethylation resulted in activation of various genes, including Laptm4b. Interestingly, KDM6B and LAPTM4B are positively correlated with EVI1 expression in patients with MDS. The EVI1/KDM6B/H3K27me3/LAPTM4B signaling pathway was also identified in EVI1hi human leukemia cell lines. We found that hyperactivation of the LAPTM4B-driven mTOR pathway was crucial for the growth of EVI1hi leukemia cells. Knockdown of Laptm4b partially rescued Evi1-induced abnormal hematopoiesis in vivo. Thus, our study establishes a mouse model to investigate EVI1hi myeloid malignancies, demonstrating the significance of the EVI1-mediated KDM6B/H3K27me3/LAPTM4B signaling axis in their maintenance.

Authors

Qiong Wu, Chunjie Yu, Fang Yu, Yiran Guo, Yue Sheng, Liping Li, Yafang Li, Yutao Zhang, Chao Hu, Jue Wang, Tong-chuan He, Yong Huang, Hongyu Ni, Zhiguang Huo, Wenshu Wu, Gang Greg Wang, Jianxin Lyu, Zhijian Qian

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Figure 1

Evi1 upregulation induces MDS/MPN–like disease in mice.

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Evi1 upregulation induces MDS/MPN–like disease in mice. (A) Schematic il...
(A) Schematic illustration of conditional Evi1-induced mouse model. (B) PCR analysis of the induction of Evi1 (LSL) and WT alleles among genomic DNA in BM cells from Mx1-Cre Tg (LSL-Evi1) mice after poly(I:C) injection. (C) Kaplan-Meier survival analysis of Evi1-OE mice and WT mice after multiple injections of poly(I:C) (50 mg per kg body weight). n = 36 per cohort, log-rank test. (D–F) Absolute numbers of white blood cells (WBC), neutrophils (NE), lymphocytes (LY), monocytes (MO), eosinophils (EO), and basophils (BA) (D) and platelets (E), as well as red blood cells (RBCs) and concentration of hemoglobin (Hb) (F), in peripheral blood (PB) from Evi1-OE mice (n = 12) and WT mice (n = 18). (G) Representative histologic analysis of PB smear (left) as well as hematoxylin and eosin–stained spleen (middle) and sternum (right) from the mice indicated. Scale bars: 10 µm (peripheral blood); 100 µm (spleen); 50 µm (sternum). Relative magnification of these images is ×4. (H–J) Analysis of frequency of Gr1+Mac1+ myeloid cells (H), B cells (I), and red cells (J) in BM cells from WT and Evi1-OE mice 3 weeks after poly(I:C) injection. n = 3 per group. Data are representative of at least 2 independent experiments and are presented as mean ± SD; 2-tailed Student’s t test, or log-rank (Mantel-Cox) test for survival curve. *P < 0.05, **P < 0.01, ***P < 0.001.