Myelodysplasia-Related Gene Mutations in Acute Myeloid Leukemia: Are All Mutations Equal? From Molecular Classification to Treatment Selection and Measurable Residual Disease

The incorporation of myelodysplasia-related gene (MRG) mutations into contemporary classifications of acute myeloid leukemia (AML) reshaped the disease stratification. The 2022 International Consensus Classification (ICC) recognizes nine MRG mutations, whereas the fifth World Health Organization classification (WHO-HAEM5) excludes RUNX1. The 2022 European LeukemiaNet (ELN) recommendations classify these mutations as adverse-risk lesions in intensively treated patients. However, emerging evidence challenges their uniform prognostic significance. Large-scale genomic analyses reveal substantial gene-specific heterogeneity, with ASXL1, RUNX1, SF3B1, and U2AF1 generally associated with adverse outcomes, whereas SRSF2 and STAG2 seem to exhibit a more favorable prognostic profile. Importantly, their clinical impact is influenced by co-mutational architecture and treatment context. Venetoclax-based regimens may attenuate the adverse prognostic impact of MRG mutations, while emerging evidence suggests potential benefits from CPX-351 in molecularly defined AML-MR. Allogeneic hematopoietic stem cell transplantation remains crucial for a curative-intent treatment, while post-transplant maintenance represents an evolving strategy. Furthermore, molecular clearance of MRG mutations during remission may provide prognostic information beyond conventional measurable residual disease assessment. This review critically examines the biological and clinical heterogeneity of MRG-mutated AML, differences across classification systems, and contemporary therapeutic approaches, including intensive chemotherapy, CPX-351, venetoclax-based regimens, transplantation, and maintenance strategies. Particular emphasis is placed on gene-specific prognostic differences, co-mutational patterns, and dynamic molecular response. Collectively, available evidence supports moving beyond a binary MRG-positive versus MRG-negative classification toward an integrated, context-dependent framework incorporating molecular characteristics, treatment exposure, and longitudinal response assessment to refine risk stratification and guide personalized therapeutic decisions.