Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia

Zhang, B. et al. (2018) Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia. Nature Medicine, 24, pp. 450-462. (doi: 10.1038/nm.4499) (PMID:29505034) (PMCID:PMC5965294)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pellicano, Dr Francesca and Holyoake, Professor Tessa and Copland, Professor Mhairi and Hopcroft, Dr Lisa
Authors: Zhang, B., Nguyen, L. X. T., Li, L., Zhao, D., Kumar, B., Wu, H., Lin, A., Pellicano, F., Hopcroft, L., Su, Y.-L., Copland, M., Holyoake, T. L., Kuo, C. J., Bhatia, R., Snyder, D. S., Ali, H., Stein, A. S., Brewer, C., Wang, H., McDonald, T., Swiderski, P., Troadec, E., Chen, C.-C., Dorrance, A., Pullarkat, V., Yuan, Y.-C., Perrotti, D., Carlesso, N., Forman, S. J., Kortylewski, M., Kuo, Y.-H., and Marcucci, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Medicine
Publisher:Nature Publishing Group
ISSN:1078-8956
ISSN (Online):1546-170X
Published Online:05 March 2018
Copyright Holders:Copyright © 2018 Nature America, Inc., part of Springer Nature
First Published:First published in Nature Medicine 24:450-462
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
498551Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CRUK)11008RI CANCER SCIENCES