Runt-Related Transcription Factor 3 Promotes Acute Myeloid Leukemia Progression.

Wenwen Zhang,Qian Ma,Dongjun Lin,Bing Long,Lingling Liu,Minyi Zhao,Zhangyi Sun

doi:10.3389/fonc.2021.725336

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with high relapse/refractory rate. Genetic and epigenetic abnormalities are driving factors for leukemogenesis. RUNX1 and RUNX2 from the Runt-related transcription factor (RUNX) family played important roles in AML pathogenesis. However, the relationship between RUNX3 and AML remains unclear. Here, we found that RUNX3 was a super-enhancer-associated gene and highly expressed in AML cells. The Cancer Genome Atlas (TCGA) database showed high expression of RUNX3 correlated with poor prognosis of AML patients. We observed that Runx3 knockdown significantly inhibited leukemia progression by inducing DNA damage to enhance apoptosis in murine AML cells. By chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we discovered that RUNX3 in AML cells mainly bound more genes involved in DNA-damage repair and antiapoptosis pathways compared to that in normal bone marrow cells. Runx3 knockdown obviously inhibited the expression of these genes in AML cells. Overall, we identified RUNX3 as an oncogene overexpressed in AML cells, and Runx3 knockdown suppressed AML progression by inducing DNA damage and apoptosis.

Highlights

Acute myeloid leukemia (AML) is one of the most common hematologic malignancies that is characterized by clonal expansion of abnormally differentiated myeloid blasts [1, 2]
We proved that RUNX3 bound and upregulated the expression of genes involved in DNA repair and antiapoptosis pathways to promote AML progression
To identify super-enhancer-associated genes that are unique in AML cells, we analyzed H3K27ac chromatin immunoprecipitation sequencing (ChIP-Seq) data of three types of normal blood cells, including neutrophils (NEs), monocytes (MOs), and hematopoietic stem cell progenitor cells (HSPCs), and AML cells (AML1#–3#)

Summary

Introduction

Acute myeloid leukemia (AML) is one of the most common hematologic malignancies that is characterized by clonal expansion of abnormally differentiated myeloid blasts [1, 2]. Genetic and epigenetic abnormalities, such as NPM1 mutation, DNMT3a mutation, and MLL rearrangement, are determinants of AML pathogenesis and always relate to AML prognosis [4]. It is imperative to further decipher the genetic and epigenetic characteristics of AML to identify more new molecular targets for AML treatment improvement. Super-enhancer is a special enhancer identified to enhance the transcription of key oncogenes in various cancer cells, such as prostate cancer cells, T cell acute lymphocytic leukemia cells, and multiple myeloma cells [5,6,7]. In mouse AML cells, some genes critical in leukemogenesis, including

Methods

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Conclusion