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

Abstract

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.

Integrative pan-cancer analysis and clinical characterization of the N7-methylguanosine (m7G) RNA modification regulators in human cancers

“…m6A, a widely studied form of RNA methylation modification, is essential for regulating RNA transcription, processing and translation, which in turn affects cellular metabolic activities. Different m6A modification patterns are known to interact with the immune phenotypes of tumors, including immune rejection, immune activation, and immune inertness, thus, estimating the m6A pattern of a tumor might enable the characterization of TME infiltration and provide guidance for improved immunotherapy strategies ( Du et al, 2021 ; Zhang et al, 2020b ). In the present study, we analyzed the correlation between m6A and m7G regulators using a deconvolution algorithm and found that most of the genes in the two groups showed a positive correlation with each other.…”

The regulation and potential roles of m6A modifications in early embryonic development and immune tolerance at the maternal-fetal interface

“…In breast cancer, the three m6A clusters (writers, erasers and readers) are correlated with subsets of the infiltrating immune landscape, including activated CD8+ T cells, NK cells, activated DCs, macrophages and Treg cells. The low m6Ascore contributes to the increased mutation burden, immune activation and survival rates and is associated with an enhanced response to anti-PD-1/PD-L1 immunotherapy (139)(140)(141). In bladder cancer, 9 m6A-related lncRNAs were dramatically associated with overall survival outcomes of bladder cancer.…”

The Potential Value of m6A RNA Methylation in the Development of Cancers Focus on Malignant Glioma

“…With the breakthroughs in the identification and understanding of m6A writers, erasers and readers, m6A methylation has been shown to affect virtually every aspect of RNA metabolism, including RNA expression, translation, splicing, decay, nuclear export, and RNA-protein interactions ( 60 , 61 ). Recently, there is growing evidence that writers, erasers and readers of m6A RNA modifications are related to multiple types of human cancers, including: gastric cancer (GC) ( 62 ), colorectal cancer (CRC) ( 63 ), breast cancer (BC) ( 64 ), lung cancer (LC) ( 65 ), hepatocellular carcinoma (HCC) ( 66 ), pancreatic cancer (PC) ( 67 ), prostate cancer (PCa) ( 68 ), acute myeloid leukemia (AML) ( 69 ), cervical cancer (CC) ( 70 ) ovarian ( 71 ) and endometrial cancer ( 72 ) (OC and EC), etc. m6A RNA methylation plays an important role in promoting CSC self-renewal, proliferation and resistance of cancer cell to radiation or chemotherapy.…”