Genetic alterations of m6A regulators predict poorer survival in acute myeloid leukemia

Abstract

Methylation of N6 adenosine (m6A) is known to be important for diverse biological processes including gene expression control, translation of protein, and messenger RNA (mRNA) splicing. However, its role in the development of human cancers is poorly understood. By analyzing datasets from the Cancer Genome Atlas Research Network (TCGA) acute myeloid leukemia (AML) study, we discover that mutations and/or copy number variations of m6A regulatory genes are strongly associated with the presence of TP53 mutations in AML patients. Further, our analyses reveal that alterations in m6A regulatory genes confer a worse survival in AML. Our work indicates that genetic alterations of m6A regulatory genes may cooperate with TP53 and/or its regulator/downstream targets in the pathogenesis and/or maintenance of AML.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0410-6) contains supplementary material, which is available to authorized users.

FTO regulates the chemo‐radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β‐catenin through mRNA demethylation

“…The m 6 A modification is one of the most common and critical mRNA modifications in human malignant diseases . More and more evidences suggest that the “writers,” “erasers,” and “readers” of m 6 A exert important role in the cancer initiation and development . As the first identified “erasers” of m 6 A, FTO was showed associated with not only the increased body mass and obesity but also the progression of various types of cancer.…”

“…It is well known that m 6 A modification is catalyzed by a methyltransferase complex consisting of “writers” proteins methyltransferase‐like 3 (METTL3) and METTL4, and “erasers” fat mass and obesity‐associated protein (FTO) and AlkB homolog 5 (ALKBH5) . Alternation of these component genes in the methyltransferase complex can give rise to a significant phenotype change, such as carcinogenesis . FTO, the first identified “eraser” of m 6 A, has been reported to play an oncogenic role in various types of cancer, including endometrial, breast, pancreatic cancer, and acute myeloid leukemia (AML), suggesting the functional importance of the mRNA m 6 A methylation and its modulators in cancer.…”

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…The mutations and CNVs of m 6 A regulatory genes were associated with poorer cytogenetic risk and other clinic‐pathological or molecular features in AML 85. In addition, impaired m 6 A regulatory genes were notably associated with the presence of TP53 mutations in AML patients and both might play a complementary role in the maintenance of AML 85. Collectively, it is unknown whether single alteration or multiple changes in m 6 A modification profoundly affect leukaemia.…”

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

“…It was reported that IGF2BP1 sustains the expression of various SRF target genes and promotes liver cancer progression in an m6A‐dependent manner . 2%–9% copy number variation (CNV) of m6A regulator genes, including METTL3 , METTL14 , YTHDF1 , YTHDF2 , ALKBH5 , and FTO , were observed in acute myeloid leukemia (AML), while patients carrying m6A‐related CNVs or mutations displayed poorer prognosis . Increased m6A enhances the expression of PTEN/c‑Myc/BCL2, modulates myeloid differentiation, haematopoietic stem/progenitor cell specification, while FTO‐mediated m6A inhibition promotes leukocyte transformation and leukemogenesis .…”

“…17 2%-9% copy number variation (CNV) of m6A regulator genes, including METTL3, METTL14, YTHDF1, YTHDF2, ALKBH5, and FTO, were observed in acute myeloid leukemia (AML), while patients carrying m6A-related CNVs or mutations displayed poorer prognosis. 18 Increased m6A enhances the expression of PTEN/c-Myc/BCL2, modulates myeloid differentiation, haematopoietic stem/progenitor cell specification, while FTO-mediated m6A inhibition promotes leukocyte transformation and leukemogenesis. [19][20][21][22] Upregulation of ALKBH5 or knockdown of METTL3/METTL14 were also reported to induce glioblastoma tumorigenesis by promoting FOXM1 expression.…”