Characterization of m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration in acute myeloid leukemia.

Previous studies have confirmed the existence of epigenetic regulation of immune responses in acute myeloid leukemia. However, the potential role of RNA N6-methyladenosine (m6A) remodeling in tumor microenvironment (TME) infiltration remains unclear. m6A patterns of 469 AML patients (420 of which provided survival data) based on 18 m6A regulators were systematically evaluated. Based on the expression of 18 m6A regulators, unsupervised agglomerative cluster analysis was applied to recognize the various m6A modification types and to classify patients. We linked these patterns to TME infiltration characteristics and identified three distinct populations of m6A modifications. These three TME cell infiltration patterns are characterized by a high degree of concordance with the three tumor immunophenotypes, which include immunoinflammatory, immunorejection, and immune inert patterns. We showed that assessment of m6A modification patterns within individually neoplasms can forecast the stage of neoplasmic inflammation, TME basal activity, subtype, hereditary mutation, and clinical patient prognosis. Limited low m6Ascore, featuring increased mutational load and immune activation, indicates an inflammatory phenotype of TME with a 5-year survival rate at 14.4% compared to the high-m6Ascore group (40.9%). Data from two different cohorts demonstrated that a higher m6Ascore showed a marked therapeutic superiority as well as clinical advantage. Assessing m6A modification patterns in AML patients could improve our knowledge of the TME infiltrative profile as well as directing effective immunotherapeutic approaches.

Han S ，Qi J ，Fang K ，Wang H ，Tang Y ，Wu D ，Han Y ... -  《Cancer Medicine》

m(6)A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer.

Zhang B ，Wu Q ，Li B ，Wang D ，Wang L ，Zhou YL ... -  《Molecular Cancer》

m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in hepatocellular carcinoma.

Huang X ，Qiu Z ，Li L ，Chen B ，Huang P ... -  《Aging-US》

m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Acute Myeloid Leukemia.

Recent studies have demonstrated epigenetic regulation of immune responses. Nevertheless, the underlying effect of RNA N6-methyladenosine (m6A) modifications on tumor microenvironment cell infiltration remains elusive. In this study, we thoroughly assessed m6A modification patterns of 255 myeloid leukemia specimens based on 23 m6A regulators. Consensus clustering of the 23 m6A regulators was performed to determine three distinct m6A modification patterns that were remarkably consistent with three immunophenotypes of tumors: immunorejection, immune activation, and immune inertness. Further evaluation and prognostic analysis of the m6A modification patterns of individual tumors revealed that low m6A score was characterized by increased mutational burden, immune activation, and survival rates, whereas high m6A score was characterized by poorer survival rates and the absence of effective immune infiltration. In addition, this study investigated the association between m6A regulators and antitumor immune responses and discovered higher expression of the immune regulators PD-L1, PD-L2, MRP1, and MRP2 in low m6A scores. Generally, the expression pattern of m6A regulators was remarkably associated with prognostic results and antitumor immune responses in acute myeloid leukemia and may be an underlying target and biological marker for immune therapies.

Du A ，Wu X ，Gao Y ，Jiang B ，Wang J ，Zhang P ，Zhao Q ... -  《Frontiers in Immunology》

m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Cell-Infiltration Characterization in Head and Neck Cancer.

Background: Recently, RNA modifications have emerged as essential epigenetic regulators of gene expression. However, the mechanism of how RNA N 6-methyladenosine (m6A) modification interacts with tumor microenvironment (TME) infiltration remains obscure. Methods: A total of 876 head and neck cancer samples considering 21 m6A regulators were included and analyzed to determine the m6A modification patterns. These modification patterns were then correlated with TME immune cell-infiltrating characteristics. A scoring system, the m6Ascore, was constructed using principal component analysis algorithms to quantify m6A modification of tumors. Results: Three m6A modification patterns were identified, with TME infiltrating characteristics highly consistent with tumors with three distinct immune phenotypes, including immune-inflamed, immune-exclude, and immune-desert phenotypes. It was demonstrated that the identification of the m6A modification patterns via m6Ascore could predict tumor progression, subtypes, TME stromal activity, variation of relevant genes, and patient prognosis. Low m6Ascore, identified to be an inflamed phenotype, is found to be associated with low stroma activity and tumor mutation burden, high survival probability, increased tumor neoantigen burden, and enhanced response to anti-PD-1/L1 immunotherapy. The therapeutic advantages and clinical benefits of patients with low m6Ascore were further verified in two immunotherapy cohorts. Conclusion: This study identified the significant role that the m6A modification played in the formation of TME characteristics. A more comprehensive understanding of the m6A modification patterns and their correlation with TME infiltration will contribute to the discovery of immunotherapy strategies with better efficacy.

Yang Q ，Xu F ，Jian A ，Yu H ，Ye T ，Hu W ... -  《Frontiers in Cell and Developmental Biology》