Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control

Abstract

N-methyladenosine (mA) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces mA modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia.

RNA m6A modification and its function in diseases

“…The overexpression levels of m 6 A modulators, such as METTL3 [68][69][70], FTO [35,36], and ALKBH5 [72], in different cases of cancers emphasize the potential therapeutic importance of targeting m 6 A modulators. To date, the in vivo functions of m 6 A system in different cell types and in different microenvironments are gradually known and will give us accumulating evidence to further define the concepts of RNA epigenetics.…”

“…m 6 A promoted the translation of c-MYC, BCL2, and PTEN mRNAs in the human AML MOLM-13 cell line [68]. In another study, METTL3 promoted the maintenance of a leukemic state by binding to the promoter of active genes, installing m 6 A modification within the target mRNA transcripts and resulting in enhanced translation of those transcripts by relieving ribosome stalling [69]. METTL3 overexpression was also observed in human hepatocellular carcinoma (HCC) and associated with poor prognosis of patients with HCC [70].…”

N6-Methyladenosine Role in Acute Myeloid Leukaemia

“…Consistent with METTL3 and METTL14 playing an oncogenic role in AML, overexpression of both genes in AML cell lines and primary blasts increased proliferation, while their downregulation impaired proliferation and resulted in a strong induction of apoptosis [51,52,53]. The oncogenic function of m 6 A was also demonstrated in primary cells derived from an AML mouse model carrying the oncogenic MLL-AF9 fusion gene and the FLT3 internal tandem duplication (FLT3-ITD), two chromosomal translocations that characterized aggressive AML subtypes and that drive AML in mouse.…”

FTO, m6Am, and the hypothesis of reversible epitranscriptomic mRNA modifications

“…Elevated m 6 A writer complex components and elevated m 6 A caused AML growth and proliferation [35,38]. Elevated m 6 A writer complex components and elevated m 6 A caused AML growth and proliferation [35,38].…”