Abstract
DNMT3A mutations are frequently identified in acute myeloid leukemia (AML) and indicate poor prognosis. Previously, we found that the hotspot mutation DNMT3A R882H could upregulate CDK1 and induce AML in conditional knock-in mice. However, the mechanism by which CDK1 is involved in leukemogenesis of DNMT3A mutation-related AML, and whether CDK1 could be a therapeutic target, remains unclear. In this study, using fluorescence resonance energy transfer and immunoprecipitation analysis, we discovered that increased CDK1 could compete with EZH2 to bind to the PHD-like motif of DNMT3A, which may disturb the protein interaction between EZH2 and DNMT3A. Knockdown of CDK1 in OCI-AML3 cells with DNMT3A mutation markedly inhibited proliferation and induced apoptosis. CDK1 selective inhibitor CGP74514A (CGP) and the pan-CDK inhibitor flavopiridol (FLA) arrested OCI-AML3 cells in the G2/M phase, and induced cell apoptosis. CGP significantly increased CD163-positive cells. Moreover, the combined application of CDK1 inhibitor and traditional chemotherapy drugs synergistically inhibited proliferation and induced apoptosis of OCI-AML3 cells. In conclusion, this study highlights CDK1 overexpression as a pathogenic factor and a potential therapeutic target for DNMT3A mutation-related AML.
Highlights
As a member of the DNA methyltransferase family, DNA-methyltransferaseDNMT3A catalyzes the transfer of methyl groups to the CpG-rich regions of active chromatin, leading to gene inactivation, and participates in cell differentiation, development, preservation of chromosomal integrity, parental imprinting, and X-chromosome inactivation [1,2]
We propose a hypothesis that there is a competitive relationship between CDK1 and EZH2 in binding DNMT3A, which might influence downstream gene regulation
We found that the mTOR–CDK1–EZH2–H3K27me3 axis is involved in the pathogenesis of DNMT3A mutation-related acute myeloid leukemia (AML) [11]
Summary
DNMT3A catalyzes the transfer of methyl groups to the CpG-rich regions of active chromatin, leading to gene inactivation, and participates in cell differentiation, development, preservation of chromosomal integrity, parental imprinting, and X-chromosome inactivation [1,2]. Somatic mutations in DNMT3A have been identified in approximately 25% of patients with acute myeloid leukemia (AML), with Arg882 (R882) being the hotspot [3,4]. DNMT3A knockout mice showed stronger self-renewal ability of hematopoietic stem cells and significantly enhanced the proliferative ability of myeloid cells [6,7]. DNMT3A R882 mutations (e.g., R882H/C) showed a dominant negative function by disturbing the formation of a tetramer with DNMT3L and inhibiting its own methyltransferase activity [8]. Lu et al reported that DNMT3A R882 mutation deregulated DNA methylation of crucial AML-promoting genes, such as Meis, Mn1, Hoxa, and Mycn [9]
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