Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia
| العنوان: | Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia |
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| المؤلفون: | Bin Zhang, Mhairi Copland, Herman Wu, Stephen J. Forman, Dandan Zhao, Ravi Bhatia, Huafeng Wang, Guido Marcucci, Le Xuan Truong Nguyen, Adrienne M. Dorrance, David S. Snyder, Piotr Swiderski, Tessa L. Holyoake, Ching-Cheng Chen, Vinod Pullarkat, Allen Lin, Bijender Kumar, Lisa E. M. Hopcroft, Tinisha McDonald, Haris Ali, Anthony S. Stein, Francesca Pellicano, Estelle Troadec, Danilo Perrotti, Nadia Carlesso, Casey J Brewer, Ya-Huei Kuo, Ling Li, Marcin Kortylewski, Calvin J. Kuo, Yu-Lin Su, Yate Ching Yuan |
| المصدر: | Nature medicine |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Fusion Proteins, bcr-abl, Down-Regulation, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Extracellular Vesicles, Mice, 03 medical and health sciences, Myelogenous, 0302 clinical medicine, Bone Marrow, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, LSC, medicine, Animals, Humans, Gene silencing, Gene Silencing, Cell Self Renewal, Stem Cell Niche, Kinase activity, Protein Kinase Inhibitors, CML, BM niche, microRNA, Gene Expression Regulation, Leukemic, Endothelial Cells, chemoresistance, General Medicine, Hematopoietic Stem Cells, medicine.disease, 3. Good health, MicroRNAs, Haematopoiesis, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Cancer research, Bone marrow, Stem cell, Chronic myelogenous leukemia |
| الوصف: | Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR–ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR–ABL, which led to inhibition of the RAN–exportin-5–RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR–ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML. |
| وصف الملف: | application/pdf |
| تدمد: | 1546-170X 1078-8956 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::eee70a03cf561424a09cec6450759e4dTest https://doi.org/10.1038/nm.4499Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....eee70a03cf561424a09cec6450759e4d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1546170X 10788956 |
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