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METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4
Chemoresistant leukemia relapse is one of the most common causes of death for acute myeloid leukemia (AML) patients and the homing/engraftment in bone marrow (BM) are crucial steps for AML cells to acquire chemoresistance by interacting with stromal cell components. No crosstalk between m(6)A modifi...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9613467/ https://www.ncbi.nlm.nih.gov/pubmed/36266324 http://dx.doi.org/10.1038/s41375-022-01696-w |
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author | Li, Mingying Ye, Jingjing Xia, Yuan Li, Meng Li, Guosheng Hu, Xiang Su, Xiuhua Wang, Dongmei Zhao, Xin Lu, Fei Li, Jingxin Ma, Daoxin Sun, Tao Ji, Chunyan |
author_facet | Li, Mingying Ye, Jingjing Xia, Yuan Li, Meng Li, Guosheng Hu, Xiang Su, Xiuhua Wang, Dongmei Zhao, Xin Lu, Fei Li, Jingxin Ma, Daoxin Sun, Tao Ji, Chunyan |
author_sort | Li, Mingying |
collection | PubMed |
description | Chemoresistant leukemia relapse is one of the most common causes of death for acute myeloid leukemia (AML) patients and the homing/engraftment in bone marrow (BM) are crucial steps for AML cells to acquire chemoresistance by interacting with stromal cell components. No crosstalk between m(6)A modification and homing/engraftment has been reported. Here, we performed comprehensive high-throughput analyses, including RNA sequencing of CR (complete remission) and relapsed AML patients, and reverse-phase protein arrays of chemoresistant cells to identify METTL3 as a key player regulating AML chemoresistance. Then, METTL3-mediated m(6)A modification was proved to induce the chemoresistance in vitro and in vivo. Furthermore, AML homing/engraftment was discovered being enhanced by upregulated-METTL3 in chemoresistant cells. And the homing/engraftment and drug-resistance associated phenotypes of chemoresistant cells could be reversed by a METTL3 inhibitor. Mechanistically, METTL3 extended the half-life of ITGA4 mRNA by m(6)A methylation, and then, increased expression of ITGA4 protein to enhance homing/engraftment of AML cells. The results provide insights into the function of m(6)A modification on the interaction between AML cells and BM niches and clarify the relationship between METTL3 and AML homing/engraftment, suggesting a therapeutic strategy for the treatment of refractory/relapsed AML with METTL3 inhibitors. [Image: see text] |
format | Online Article Text |
id | pubmed-9613467 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96134672022-10-29 METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4 Li, Mingying Ye, Jingjing Xia, Yuan Li, Meng Li, Guosheng Hu, Xiang Su, Xiuhua Wang, Dongmei Zhao, Xin Lu, Fei Li, Jingxin Ma, Daoxin Sun, Tao Ji, Chunyan Leukemia Article Chemoresistant leukemia relapse is one of the most common causes of death for acute myeloid leukemia (AML) patients and the homing/engraftment in bone marrow (BM) are crucial steps for AML cells to acquire chemoresistance by interacting with stromal cell components. No crosstalk between m(6)A modification and homing/engraftment has been reported. Here, we performed comprehensive high-throughput analyses, including RNA sequencing of CR (complete remission) and relapsed AML patients, and reverse-phase protein arrays of chemoresistant cells to identify METTL3 as a key player regulating AML chemoresistance. Then, METTL3-mediated m(6)A modification was proved to induce the chemoresistance in vitro and in vivo. Furthermore, AML homing/engraftment was discovered being enhanced by upregulated-METTL3 in chemoresistant cells. And the homing/engraftment and drug-resistance associated phenotypes of chemoresistant cells could be reversed by a METTL3 inhibitor. Mechanistically, METTL3 extended the half-life of ITGA4 mRNA by m(6)A methylation, and then, increased expression of ITGA4 protein to enhance homing/engraftment of AML cells. The results provide insights into the function of m(6)A modification on the interaction between AML cells and BM niches and clarify the relationship between METTL3 and AML homing/engraftment, suggesting a therapeutic strategy for the treatment of refractory/relapsed AML with METTL3 inhibitors. [Image: see text] Nature Publishing Group UK 2022-10-20 2022 /pmc/articles/PMC9613467/ /pubmed/36266324 http://dx.doi.org/10.1038/s41375-022-01696-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Li, Mingying Ye, Jingjing Xia, Yuan Li, Meng Li, Guosheng Hu, Xiang Su, Xiuhua Wang, Dongmei Zhao, Xin Lu, Fei Li, Jingxin Ma, Daoxin Sun, Tao Ji, Chunyan METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4 |
title | METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4 |
title_full | METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4 |
title_fullStr | METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4 |
title_full_unstemmed | METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4 |
title_short | METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4 |
title_sort | mettl3 mediates chemoresistance by enhancing aml homing and engraftment via itga4 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9613467/ https://www.ncbi.nlm.nih.gov/pubmed/36266324 http://dx.doi.org/10.1038/s41375-022-01696-w |
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