New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia.
New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia.
复制标题
对慢性髓细胞白血病中胃L3在维持异常翻译中的催化依赖性和非依赖性作用的新认识。
DOI：
10.1038/s41419-021-04169-7
复制
发表时间：
2021-09-24
影响因子：
9
通讯作者：
Fatica A
中科院分区：
文献类型：
--
作者：
Ianniello Z;Sorci M;Ceci Ginistrelli L;Iaiza A;Marchioni M;Tito C;Capuano E;Masciarelli S;Ottone T;Attrotto C;Rizzo M;Franceschini L;de Pretis S;Voso MT;Pelizzola M;Fazi F;Fatica A
慢性髓性白血病（CML）是一种骨髓增生性肿瘤，由酪氨酸激酶BCR-ABL1融合蛋白的存在引起，酪氨酸激酶BCR-ABL1融合蛋白的转录和mRNA翻译失调。酪氨酸激酶抑制剂（TKIs）是首选治疗方法。然而，对TKIs的耐药性仍然是治疗CML患者的一个挑战。在这里，我们发现m6A甲基转移酶复合物METTL3/METTL14在CML患者中上调，这是原代CML细胞和对TKI伊马替尼敏感和耐药的CML细胞系增殖所必需的。我们证明了METTL3的耗尽严重损害了全局翻译效率。特别是，我们的数据表明，METTL3对于参与核糖体生物发生和翻译的基因的表达至关重要。具体来说，我们发现METTL3直接调节几种肿瘤中被鉴定为致癌基因的PES1蛋白的水平。我们提出了一个模型，其中核METTL3/METTL14甲基转移酶复合物修饰新生转录本，其翻译通过METTL3的细胞质定位而增强，而不依赖于其催化活性。总之，我们的研究结果表明，METTL3是CML中一个新的相关癌基因，也是TKI耐药CML的一个有希望的治疗靶点。
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.
登录
查看更多内容
影响因子：
--
作者：
Mangiavacchi A;Sorci M;Masciarelli S;Larivera S;Legnini I;Iosue I;Bozzoni I;Fazi F;Fatica A
通讯作者：
Fatica A
影响因子：
10.5
作者：
Lasman L;Krupalnik V;Viukov S;Mor N;Aguilera-Castrejon A;Schneir D;Bayerl J;Mizrahi O;Peles S;Tawil S;Sathe S;Nachshon A;Shani T;Zerbib M;Kilimnik I;Aigner S;Shankar A;Mueller JR;Schwartz S;Stern-Ginossar N;Yeo GW;Geula S;Novershtern N;Hanna JH
通讯作者：
Hanna JH
DOI：
10.1126/science.aao2793
发表时间：
2018-05-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Muhar M;Ebert A;Neumann T;Umkehrer C;Jude J;Wieshofer C;Rescheneder P;Lipp JJ;Herzog VA;Reichholf B;Cisneros DA;Hoffmann T;Schlapansky MF;Bhat P;von Haeseler A;Köcher T;Obenauf AC;Popow J;Ameres SL;Zuber J
通讯作者：
Zuber J
影响因子：
5.6
作者：
Ianniello Z;Fatica A
通讯作者：
Fatica A
影响因子：
16
作者：
Lapik, YR;Fernandes, CJ;Pestov, DG
通讯作者：
Pestov, DG