EZH2/EHMT2 Histone Methyltransferases Inhibit the Transcription of DLX5 and Promote the Transformation of Myelodysplastic Syndrome to Acute Myeloid Leukemia.

Zhuanzhen Zheng,Ling Li,Guoxia Li,Yaofang Zhang,Fanggang Ren,Chunxia Dong,Wenliang Chen,Yanping Ma

doi:10.3389/fcell.2021.619795

Abstract

Myelodysplastic syndrome (MDS) is characterized by clonal hematopoiesis and impaired differentiation, and may develop to acute myeloid leukemia (AML). We explored the mechanism of histone methyltransferase EZH2/EHMT2 during the transformation of MDS into AML. Expression of EZH2/EHMT2 in patients and NHD13 mice was detected. EZH2 and EHMT2 were silenced or overexpressed in SKM-1 cells. The cell proliferation and cycle were evaluated. Levels of DLX5, H3K27me3, and H3K9me2 in SKM-1 cells were detected. Binding of DLX5 promoter region to H3K27me3 and H3K9me2 was examined. Levels of H3K27me3/H3K9me2 were decreased by EZH2/EHMT2 inhibitor (EPZ-6438/BIX-01294), and changes of DLX5 expression and cell proliferation were observed. EZH2 was poorly expressed in MDS patients but highly expressed in MDS-AML patients. EHMT2 was promoted in both MDS and MDS-AML patients. EZH2 expression was reduced and EHMT2 expression was promoted in NHD13 mice. NHD13 mice with overexpressing EZH2 or EHMT2 transformed into AML more quickly. Intervention of EZH2 or EHMT2 inhibited SKM-1 cell proliferation and promoted DLX5 expression. When silencing EZH1 and EZH2 in SKM-1 cells, the H3K27me3 level was decreased. EZH2 silencing repressed the proliferation of SKM-1 cells. Transcription level of DLX5 in SKM-1 cells was inhibited by H3K27me3 and H3K9me2. Enhanced DLX5 repressed SKM-1 cell proliferation. In conclusion, EZH2/EHMT2 catalyzed H3K27me3/H3K9me2 to inhibit the transcription of DLX5, thus promoting the transformation from MDS to AML.

Highlights

Myelodysplastic syndrome (MDS) comprises a group of heterogeneous myeloid neoplasms sharing the common characteristics of bone marrow failure, including hematopoietic dysfunction, morphologic dysplasia, and peripheral blood cell reduction (Ogawa, 2019)
Comparing the two groups of mice, it was found that NHD13 mice with high expression of EZH2 transformed from MDS to acute myeloid leukemia (AML) in a short period of time, while the mice with low expression of EZH2 took a relatively long time to transform into AML, even without the presence of AML transformation (Figure 2C)
It was found that mice with high expression of EHMT2 developed from MDS to AML more quickly (Figure 2D), and the survival rate of NHD13 mice with high expression of EHMT2 was significantly reduced (p < 0.05; Figure 2F)

Summary

Introduction

Myelodysplastic syndrome (MDS) comprises a group of heterogeneous myeloid neoplasms sharing the common characteristics of bone marrow failure, including hematopoietic dysfunction, morphologic dysplasia, and peripheral blood cell reduction (Ogawa, 2019). Role of EZH2/EHMT2 in MDS abnormalities, usually develop rapidly into acute myeloid leukemia (AML) and eventually die of the disease in the absence of bone marrow transplantation (Griffiths and Gore, 2013). AML is a completely malignant and aggressive blood cancer, featured by the extensive accumulation of developmentally arrested and immature blasts in bone marrow (Platzbecker et al, 2017). NHD13 mouse is an animal model of MDS based on NUP98Hoxd fusion gene, which has the key characteristics of MDS and may have leukemia transformation within 14 months, and it is often used in medical research (Lin et al, 2005; Slape et al, 2008). The overexpression of EZH2 may be a potential biomarker for the transformation of MDS to AML

Methods

Results

Conclusion