Evi1 Governs Kdm6b-mediated Histone Demethylation to Regulate the Laptm4b-driven MTOR Pathway in Hematopoietic Progenitor Cells

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2024 Dec 16

PMID 39680456

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

Affiliations

Soon will be listed here.

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.

References

He F, Ni N, Zeng Z, Wu D, Feng Y, Li A . FAMSi: A Synthetic Biology Approach to the Fast Assembly of Multiplex siRNAs for Silencing Gene Expression in Mammalian Cells. Mol Ther Nucleic Acids. 2020; 22:885-899. PMC: 7658575. DOI: 10.1016/j.omtn.2020.10.007. View

Wang W, Cortes J, Lin P, Beaty M, Ai D, Amin H . Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors. Blood. 2015; 126(14):1699-706. PMC: 4624442. DOI: 10.1182/blood-2015-05-646489. View

Zhou T, Kinney M, Scott L, Zinkel S, Rebel V . Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research. Blood. 2015; 126(9):1057-68. PMC: 4551359. DOI: 10.1182/blood-2015-01-624239. View

Wilson M, Tsakraklides V, Tran M, Xiao Y, Zhang Y, Perkins A . EVI1 Interferes with Myeloid Maturation via Transcriptional Repression of Cebpa, via Binding to Two Far Downstream Regulatory Elements. J Biol Chem. 2016; 291(26):13591-607. PMC: 4919445. DOI: 10.1074/jbc.M115.708156. View

Nimer S . Myelodysplastic syndromes. Blood. 2008; 111(10):4841-51. DOI: 10.1182/blood-2007-08-078139. View

Kataoka K, Sato T, Yoshimi A, Goyama S, Tsuruta T, Kobayashi H . Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity. J Exp Med. 2011; 208(12):2403-16. PMC: 3256960. DOI: 10.1084/jem.20110447. View

Kreider B, Orkin S, Ihle J . Loss of erythropoietin responsiveness in erythroid progenitors due to expression of the Evi-1 myeloid-transforming gene. Proc Natl Acad Sci U S A. 1993; 90(14):6454-8. PMC: 46950. DOI: 10.1073/pnas.90.14.6454. View

Tanaka T, Nishida J, Mitani K, Ogawa S, Yazaki Y, Hirai H . Evi-1 raises AP-1 activity and stimulates c-fos promoter transactivation with dependence on the second zinc finger domain. J Biol Chem. 1994; 269(39):24020-6. View

Swigut T, Wysocka J . H3K27 demethylases, at long last. Cell. 2007; 131(1):29-32. DOI: 10.1016/j.cell.2007.09.026. View

10.

Skene P, Henikoff J, Henikoff S . Targeted in situ genome-wide profiling with high efficiency for low cell numbers. Nat Protoc. 2018; 13(5):1006-1019. DOI: 10.1038/nprot.2018.015. View

11.

Summerer I, Haferlach C, Meggendorfer M, Kern W, Haferlach T, Stengel A . Prognosis of ()-rearranged MDS and AML patients rather depends on accompanying molecular mutations than on blast count. Leuk Lymphoma. 2020; 61(7):1756-1759. DOI: 10.1080/10428194.2020.1737689. View

12.

Park W, Hong B, Lee J, Choi C, Kim M . H3K27 Demethylase JMJD3 Employs the NF-κB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote Melanoma Progression and Metastasis. Cancer Res. 2016; 76(1):161-70. DOI: 10.1158/0008-5472.CAN-15-0536. View

13.

Molnar L, Berki T, Hussain A, Nemeth P, Losonczy H . Detection of TNFalpha expression in the bone marrow and determination of TNFalpha production of peripheral blood mononuclear cells in myelodysplastic syndrome. Pathol Oncol Res. 2000; 6(1):18-23. DOI: 10.1007/BF03032653. View

14.

Vinatzer U, Taplick J, Seiser C, Fonatsch C, Wieser R . The leukaemia-associated transcription factors EVI-1 and MDS1/EVI1 repress transcription and interact with histone deacetylase. Br J Haematol. 2001; 114(3):566-73. DOI: 10.1046/j.1365-2141.2001.02987.x. View

15.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

16.

Langmead B, Trapnell C, Pop M, Salzberg S . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10(3):R25. PMC: 2690996. DOI: 10.1186/gb-2009-10-3-r25. View

17.

Morishita K, Parganas E, Matsugi T, Ihle J . Expression of the Evi-1 zinc finger gene in 32Dc13 myeloid cells blocks granulocytic differentiation in response to granulocyte colony-stimulating factor. Mol Cell Biol. 1992; 12(1):183-9. PMC: 364082. DOI: 10.1128/mcb.12.1.183-189.1992. View

18.

Laricchia-Robbio L, Premanand K, Rinaldi C, Nucifora G . EVI1 Impairs myelopoiesis by deregulation of PU.1 function. Cancer Res. 2009; 69(4):1633-42. DOI: 10.1158/0008-5472.CAN-08-2562. View

19.

Lugthart S, Figueroa M, Bindels E, Skrabanek L, Valk P, Li Y . Aberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1. Blood. 2010; 117(1):234-41. PMC: 3037746. DOI: 10.1182/blood-2010-04-281337. View

20.

Lu Y, Liang Y, Zheng X, Deng X, Huang W, Zhang G . EVI1 promotes epithelial-to-mesenchymal transition, cancer stem cell features and chemo-/radioresistance in nasopharyngeal carcinoma. J Exp Clin Cancer Res. 2019; 38(1):82. PMC: 6377731. DOI: 10.1186/s13046-019-1077-3. View