The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability

Ying Chen,Yan Shen,Jianchuan Deng,Nan Zhang,Shifeng Lou,Huan Li,Ping Zhang

doi:10.1038/s12276-022-00735-x

Abstract

N6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), a subtype of leukemia associated with poor prognosis and high genetic risk. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 dramatically suppresses the apoptosis, reduces the proliferation, and impairs the leukemic capacity of AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-modified RNA. Thus, we provided compelling evidence demonstrating that the m6A reader IGF2BP3 contributes to tumorigenesis and poor prognosis in AML and can serve as a target for the development of cancer therapeutics.

Highlights

Leukemia is caused by genetic mutations and chromosomal aberrations that alter the growth and differentiation program of hematopoietic cells[1]
In the TCGAAML cohort, high expression of IGF2BP3 was associated with shorter overall survival times in patients with acute myeloid leukemia (AML) (HR = 2.578, 95% CI = 1.444–4.602, P = 0.001), and high expression of HNRNPA2B1 was associated with longer overall survival times in patients with AML (HR = 0.991, 95% CI = 0.982–0.999, P = 0.027)
In the OHSU-AML cohort, high expression of IGF2BP3 was associated with poor overall prognosis of AML (HR = 1.114, 95% CI = 1.006–1.233, P = 0.038), and HNRNPA2B1 expression was not associated with overall survival in patients with AML (P = 0.421)

Summary

Introduction

Leukemia is caused by genetic mutations and chromosomal aberrations that alter the growth and differentiation program of hematopoietic cells[1]. In the last few decades, epigenetic modifications (such as DNA methylation and histone modifications) have been found to play an important role in this process, and they are currently therapeutic targets in acute myeloid leukemia (AML) and other hematologic malignancies[2]. METTL3, an m6A methyltransferase, is highly expressed in AML. It activates the oncogene c-MYC by enhancing m6A modification of SP1 and promotes the occurrence of AML by regulating the translation of BCL2 and PTEN mRNAs through m6A modification[11,12]. FTO and ALKBH5, m6A demethylases, are abnormally expressed in AML and promote tumorigenesis and self-renewal of leukemia stem cells through m6A-dependent regulation of their target mRNAs13–15. The role of various m6A reader proteins in the progression of leukemia remains largely unexplored

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