The role of m6A RNA methyltransferase METTL3 in drug resistance mechanisms in acute myeloid leukemia

TL;DR

This paper reviews how METTL3, an RNA methyltransferase, contributes to drug resistance in acute myeloid leukemia and explores new treatment strategies targeting it.

Contribution

The paper uniquely integrates METTL3's role in m6A modifications with noncoding RNA regulation, autophagy, and niche adaptation in drug resistance.

Findings

METTL3 stabilizes and promotes translation of resistance-associated genes like BCL2, MCL1, and MYC in AML.

Pharmacological METTL3 inhibition with STM2457 and PROTACs reverses resistance in preclinical models.

METTL3 influences noncoding RNA, autophagy, and metabolic-epigenetic crosstalk, linking to broader resistance pathways.

Abstract

This review examines the role of METTL3, a core RNA methyltransferase, in therapeutic resistance in acute myeloid leukemia (AML) and discusses emerging strategies to address this challenge. METTL3 regulates N6-methyladenosine (m6A) modifications on transcripts involved in key cellular processes, including apoptosis (BCL2, MCL1), metabolism (PGC-1α, CSRP1), proliferation (MYC), autophagy (FOXO3), and bone marrow microenvironmental interactions (ITGA4, AKT1). These modifications enhance the stability and translation of resistance-associated genes, supporting leukemic cell survival under treatment pressure. Pharmacological targeting of METTL3 has shown efficacy in preclinical AML models. Inhibitors such as STM2457, METTL3-directed PROTACs, and rational drug combinations with agents including venetoclax, anthracyclines, and ATRA, have reversed resistance phenotypes and impaired leukemic cell fitness. Beyond canonical resistance mechanisms, METTL3 also regulates noncoding RNAs, autophagy, and metabolic–epigenetic crosstalk, including histone lactylation, linking epitranscriptomic regulation to broader resistance pathways. By integrating molecular, cellular, and microenvironmental evidence, this review underscores METTL3 as a central driver of drug resistance and a promising therapeutic target in relapsed or refractory AML. Unlike previous summaries, it highlights the convergence of METTL3-mediated m6A modifications with noncoding RNA regulation, autophagy, and niche adaptation, and critically evaluates emerging therapeutic approaches, including catalytic inhibitors, PROTACs, and natural compounds.

Figures