CBFB-MYH11 Fusion Sequesters RUNX1 in Cytoplasm to Prevent DNMT3A Recruitment to Target Genes in AML.

Peng Liu,Mengyu Zhou,Yingjie Ai,Jin-Pin Liu,Yun Gao,Hai-Xin Yuan,Yiping Sun,Si-Jia Sun,Xiufei Chen,Yun Liu,Yue Xiong

doi:10.3389/fcell.2021.675424

Abstract

A growing number of human diseases have been found to be associated with aberrant DNA methylation, including cancer. Mutations targeting genes encoding DNA methyltransferase (DNMT), TET family of DNA demethylases, and isocitrate dehydrogenase (IDH1, IDH2) that produce TET inhibitory metabolite, 2-hyoxyglutarate (2-HG), are found in more than half of acute myeloid leukemia (AML). To gain new insights into the regulation of DNA de/methylation and consequence of its alteration in cancer development, we searched for genes which are mutated in a manner that is linked with gene mutations involved in DNA de/methylation in multiple cancer types. We found that recurrent CBFB-MYH11 fusions, which result in the expression of fusion protein comprising core-binding factor β (CBFB) and myosin heavy chain 11 (MYH11) and are found in 6∼8% of AML patients, occur mutually exclusively with DNMT3A mutations. Tumors bearing CBFB-MYH11 fusion show DNA hypomethylation patterns similar to those with loss-of-function mutation of DNMT3A. Expression of CBFB-MYH11 fusion or inhibition of DNMT3A similarly impairs the methylation and expression of target genes of Runt related transcription factor 1 (RUNX1), a functional partner of CBFB. We demonstrate that RUNX1 directly interacts with DNMT3A and that CBFB-MYH11 fusion protein sequesters RUNX1 in the cytoplasm, thereby preventing RUNX1 from interacting with and recruiting DNMT3A to its target genes. Our results identify a novel regulation of DNA methylation and provide a molecular basis how CBFB-MYH11 fusion contributes to leukemogenesis.

Highlights

Epigenetic modification plays critical roles in many cellular processes, such as development, differentiation and hemostasis, and, when dysregulated, leads to disease states including cancer
To identify new gene(s) that is potentially involved in the regulation of DNA de/methylation process (Figure 1A), we performed a comprehensive analysis of mutations targeting three families of genes which are known to be involved in DNA de/methylation; two IDH genes (IDH1 and IDH2), three TET genes (TET1, TET2, and TET3) and four DNA methyltransferase (DNMT) genes (DNMT3A, DNMT3B, DNMT3L, and DNMT1) in 34 cancer types
We found that these three families of genes were mainly mutated in 10 cancer types; bladder urothelial carcinoma (BLCA), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), glioblastoma multiforme (GBM), acute myeloid leukemia (AML), brain lower grade glioma (LGG), lung adenocarcinoma (LUAD), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC) (Figure 1B)

Summary

Introduction

Epigenetic modification plays critical roles in many cellular processes, such as development, differentiation and hemostasis, and, when dysregulated, leads to disease states including cancer. Reversible DNA methylation is one of the major epigenetic modifications that can activate or repress gene expression (Jones, 2012; Yang et al, 2014). Frequent mutations have been found targeting the enzymes involved in both DNA methylation (DNA methyltransferase, predominantly DNMT3A) (Yang et al, 2015) and DNA demethylation [the TET family α-KG/Fe(II)-dependent DNA dioxygenases, mostly TET2] (Rasmussen and Helin, 2016; Lio et al, 2019). Frequent mutations are found in the genes involved in the regulation of DNA de/methylation function. Mutations targeting transcriptional factor WT1 disrupt its binding with TET2 and impair its recruitment of TET2 in gene regulation (Rampal et al, 2014; Wang et al, 2015)

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Conclusion