Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells
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
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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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 3

Evi1-induced MDS/MPN is transplantable.

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Evi1-induced MDS/MPN is transplantable. (A) Absolute numbers of WBCs, NE...
(A) Absolute numbers of WBCs, NEs, LYs, and RBCs as well as concentration of Hb and platelets (PLT) in PB from Evi1-OE and WT recipient mice. n = 6 for WT group, n = 4 for Evi1-OE group. (B) Flow cytometric analysis of the total number of Lin– cells, HPCs, and subsets of myeloid progenitors including CMPs, GMPs, and MEPs in the mice indicated in A. (C) Frequency of Gr1+Mac1+cells in BM and spleen from the mice indicated in A. (D) Frequency of the subsets of B cells in BM cells. (E) Schematic illustration of the competitive transplantation assay. (F) The relative ratio of donor-derived cells (CD45.1–CD45.2+) to competitor-derived cells (CD45.1+CD45.2+) in PB from the recipient mice. (G–I) The relative ratio of donor-derived cells to competitor-derived cells in CD3e+ cells (G), B220+ cells (H), and myeloid cells (I) in PB. n = 5 for WT group, n = 6–7 for Evi1-OE group in F–I. (J) Representative flow cytometry plots for the donor and competitor cells before injection and at the fourth month of transplantation. (K) The relative ratio of donor-derived cells to competitor-derived cells in the total BM cells and different lineage cells in BM. (L) The relative ratio of donor-derived cells to competitor-derived cells in different populations as indicated in BM. n = 4 for WT group, n = 7 for Evi1-OE group in K and L. All data are representative of at least 2 independent experiments and are expressed as mean ± SD; 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.