Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m6A methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML.
Highlights
Chronic myeloid leukemia (CML) is associated in about 95% of patients with a translocation between chromosome 9 and 22 that results in the production of the oncogenic BCR-ABL1 fusion gene [1]
We show that the impact of METTL3 on mRNA translation depends on its localization in the cytoplasm and is independent from its catalytic activity
The METTL3/METTL14 complex is upregulated in CML METTL3 and METTL14 are upregulated in acute myeloid leukemia (AML) where they have an established oncogenic function and play a relevant role in AML survival [30,31,32]
Summary
Chronic myeloid leukemia (CML) is associated in about 95% of patients with a translocation between chromosome 9 and 22 that results in the production of the oncogenic BCR-ABL1 fusion gene [1]. Abl is a protein tyrosine kinase that is constitutively activated in the BCR-ABL1 fusion resulting in the alteration of multiple signaling pathways that regulate gene expression [2]. The use of ABL1 tyrosine kinase inhibitors (TKIs) made CML clinically manageable and curable. Progress has been made in the understanding of signal transduction in the BCR-ABL1-mediated transformation, the role of m6A in CML remains unknown. The major complex responsible for m6A modification within mRNA is the METTL3/METTL14 complex [9]. In lung cancer METTL3 localized to the cytoplasm, where it can act as m6A reader and promotes translation of m6A modified mRNAs [10, 11]
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