Epigenetic silencing of UBXN8 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

Erna Yang,Desheng Gong,Jieying Li,Yonghui Li,Synat Kang,Xuefeng Gao,Juan Zhang,Li Yu,Hong Wang,Caixia Han,Wei Guan

doi:10.1038/s12276-021-00695-8

Abstract

The formation of the RUNX1-RUNX1T1 fusion protein, resulting from the t(8;21) translocation, is considered to be one of the initiating events of t(8;21) acute myeloid leukemia (AML). However, the mechanisms of the oncogenic mechanism of RUNX1-RUNX1T1 remain unclear. In this study, we found that RUNX1-RUNX1T1 triggers the heterochromatic silencing of UBXN8 by recognizing the RUNX1-binding sites and recruiting chromatin-remodeling enzymes to the UBXN8 promoter region. Decitabine, a specific inhibitor of DNA methylation, upregulated the expression of UBXN8 in RUNX1-RUNX1T1+ AML cell lines. Overexpression of UBXN8 inhibited the proliferation and colony-forming ability of and promoted cell cycle arrest in t(8;21) AML cell lines. Enhancing UBXN8 levels can significantly inhibit tumor proliferation and promote the differentiation of RUNX1-RUNX1T1+ cells in vivo. In conclusion, our results indicated that epigenetic silencing of UBXN8 via methylation of its promoter region mediated by the RUNX1-RUNX1T1 fusion protein contributes to the leukemogenesis of t(8;21) AML and that UBXN8 targeting may be a potential therapeutic strategy for t(8;21) AML.

Highlights

The t(8;21)(q22;q22) translocation is one of the most common chromosomal aberrations in acute myeloid leukemia (AML), and this abnormality is predominantly present in the AML FrenchAmerican-British (FAB)-M2 subtype[1]
These results were subsequently validated in the public database BloodSpot, which included 4 normal monocyte lines, 98 t(8;21) AML samples, 87 t(15;17) AML samples, 77 inv (16)/t(16;16) AML samples, 58 t(11q23)/MLL samples, and 87 complex aberrant karyotype AML samples, revealing a significant downregulation of UBXN8 expression in t(8;21) AML compared to the other subtypes of AML and healthy monocytes (Fig. 1c)
From the published GEO microarray dataset (GSE13159), we found that the expression of UBXN8 had a markedly negative relationship with the expression of RUNX1RUNX1T1 in t(8;21) AML (Fig. 1d)

Summary

Introduction

The t(8;21)(q22;q22) translocation is one of the most common chromosomal aberrations in acute myeloid leukemia (AML), and this abnormality is predominantly present in the AML FrenchAmerican-British (FAB)-M2 subtype[1]. Since the discovery of the RUNX1-RUNX1T1 fusion protein, numerous studies have revealed that t(8;21) AML is a highly heterogeneous disease from a biological and a clinical point of view[2]. Recent genome-wide studies identified unique DNA methylation signatures for subsets of AML patients, indicating that t(8;21) AML patients have a unique methylation pattern and that such an abnormal methylation pattern leads to aberrant expression of the gene, which plays an important role in the occurrence and development of this disease[3,4]. Among the UBX protein family members, UBXN8 was identified as a new tumor suppressor candidate that functions in a TP53-dependent manner in hepatocellular carcinoma (HCC)[10]

Methods

Results

Conclusion