One Stone, Two Birds: N6-Methyladenosine RNA Modification in Leukemia Stem Cells and the Tumor Immune Microenvironment in Acute Myeloid Leukemia.

Acute myeloid leukemia is the most common acute leukemia in adults, with accumulation of abundant blasts and impairment of hematogenic function. Despite great advances in diagnosis and therapy, the overall survival of patients with acute myeloid leukemia remains poor. Leukemia stem cells are the root cause of relapse and chemoresistance in acute myeloid leukemia. The tumor immune microenvironment is another trigger to induce recurrence and drug resistance. Understanding the underlying factors influencing leukemia stem cells and the tumor immune microenvironment is an urgent and unmet need. Intriguingly, N6-methyladenosine, the most widespread internal mRNA modification in eukaryotes, is found to regulate both leukemia stem cells and the tumor immune microenvironment. Methyltransferases and demethylases cooperatively make N6-methyladenosine modification reversible and dynamic. Increasing evidence demonstrates that N6-methyladenosine modification extensively participates in tumorigenesis and progression in various cancers, including acute myeloid leukemia. In this review, we summarize the current progress in studies on the functions of N6-methyladenosine modification in acute myeloid leukemia, especially in leukemia stem cells and the tumor immune microenvironment. We generalize the landscape of N6-methyladenosine modification in self-renewal of leukemia stem cells and immune microenvironment regulation, as well as in the initiation, growth, proliferation, differentiation, and apoptosis of leukemia cells. In addition, we further explore the clinical application of N6-methyladenosine modification in diagnosis, prognostic stratification, and effect evaluation. Considering the roles of N6-methyladenosine modification in leukemia stem cells and the tumor immune microenvironment, we propose targeting N6-methyladenosine regulators as one stone to kill two birds for acute myeloid leukemia treatment.