New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia
| العنوان: | New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia |
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| المؤلفون: | Marcella Marchioni, Melissa Sorci, Mattia Pelizzola, Silvia Masciarelli, Francesco Fazi, Lavinia Ceci Ginistrelli, Cristina Attrotto, Alessandro Fatica, Alessia Iaiza, Ernestina Capuano, Claudia Tito, Manuela Rizzo, Zaira Ianniello, Tiziana Ottone, Luca Franceschini, Maria Teresa Voso, Stefano de Pretis |
| المصدر: | Cell Death & Disease Cell Death and Disease, Vol 12, Iss 10, Pp 1-12 (2021) |
| بيانات النشر: | SPRINGERNATURE, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Adenosine, Messenger, Drug Resistance, Ribosome biogenesis, translation, Models, hemic and lymphatic diseases, Chronic, Tumor, leukemia, Myeloid leukemia, RNA-Binding Proteins, Translation (biology), Ribosome, Up-Regulation, Gene Knockdown Techniques, Imatinib Mesylate, Settore BIO/17 - ISTOLOGIA, Tyrosine kinase, medicine.drug, RNA modification, Cell Survival, Immunology, Biology, Models, Biological, Article, Catalysis, Cell Line, Proto-Oncogene Proteins c-myc, Cellular and Molecular Neuroscience, Cell Line, Tumor, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Humans, RNA, Messenger, Myeloproliferative neoplasm, Chronic myeloid leukaemia, Cell Proliferation, Cell Nucleus, QH573-671, Methyltransferase complex, Imatinib, Cell Biology, Methyltransferases, medicine.disease, Biological, Settore MED/15, Fusion protein, Drug Resistance, Neoplasm, Protein Biosynthesis, Cancer research, Neoplasm, RNA, BCR-ABL Positive, Cytology, Myelogenous |
| الوصف: | 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. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::94d6b7c542fdee56c74ea3a910678c8d http://hdl.handle.net/2108/283255 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....94d6b7c542fdee56c74ea3a910678c8d |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |