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

By I. Barbieri, K. Tzelepis, Luca Pandolfini, Junwei Shi, Gonzalo Millán-Zambrano, S. Robson, Demetrios Aspris, Valentina Migliori, Andrew J. Bannister, N. Han and 6 more. Nature, 2017

982 citations recorded by the source corpus.

N6-methyladenosine (m6A) 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 m6A 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4ecf6483dcae2ae7d27b88271d7e1c04351c02a2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Chuan He
2. Hailing Shi
3. Samie R. Jaffrey

In Molecular Biology

1. Chuan He
2. Samie R. Jaffrey
3. S. Zaccara
4. Hailing Shi
5. Jiangbo W
6. Syuzo Kaneko
7. Masaaki Komatsu
8. Ken Asada

Citations in the corpus

• RNA N6-methyladenosine modification in cancers: current status and perspectives (2018, background): “Nonetheless, METTL3 may also have other functions independent of its catalytic activity in lung cancer, although such function was not reported in AML.(27,82,83) Thus, development of inhibitors to target METTL3’s catalytic activity may not be sufficient to inhibit its overall functions.”
• Functions of N6-methyladenosine and its role in cancer (2019, background): “METTL3 SP1 translation promotes cell proliferation and inhibits cell differentiation [119]”
• Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia (2019, background): “METTL3 and METTL14, the m6A methyltransferases, have been reported to control and/or maintain myeloid leukemia, highlighting their oncogenic roles in leukemogenesis (Barbieri et al., 2017; Vu et al., 2017; Weng et al., 2018).”
• Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection (2020, background): “METTL3 is associated with the m6A modified transcription factor CCAAT enhancer binding protein zeta (CEBPZ), and is required for the growth of AML cells [73].”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “A recent study in acute myeloid leukemia cells showed that a fraction of METTL3 associates with the promoter regions of ~80 active genes specified by a transcription factor CCAAT enhancer binding protein zeta (CEBPZ) independent of METTL14 (Barbieri et al., 2017).”
• A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA (2020, methodology): “The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells.”
• Targeting FTO suppresses cancer stem cell maintenance and immune evasion (2020, positive): “Similar to FTO, m6A writers (METTL3/14) also target MYC and play oncogenic roles in AML (Barbieri et al., 2017; Vu et al., 2017; Weng et al., 2018), likely through distinct mechanisms (Deng et al., 2018c).”
• The potential role of RNA N6-methyladenosine in Cancer progression (2020, background): “Promoter-bound METTL3 induced m6A modification within the coding region of the related mRNA transcripts and enhanced the translation of these transcripts by removing the stalled ribosomes [146].”
• RNA modifications detection by comparative Nanopore direct RNA sequencing (2019, neutral): “qRT-PCR primers: 7sk (22-73): Fwd 5′-GCGACATCTGTCACCC CATT-3′; Rev 5′-CAGCCAGATCAGCCGAATCA-3′.”
• RNA modifications modulate gene expression during development (2018, positive): “These effects could be mediated by changes in the methylation of cell-state specific transcripts such as MYC , MYB , BCL2 , PTEN , and SP1 that help to maintain self-renewal and prevent differentiation ( 56-58 ).”