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

Bin Zhang, Le Xuan Truong Nguyen, Ling Li, Dandan Zhao, Bijender Kumar, Herman Wu, Allen Lin, Francesca Pellicano, Lisa Hopcroft, Yu Lin Su, Mhairi Copland, Tessa L. Holyoake, Calvin J. Kuo, Ravi Bhatia, David S. Snyder, Haris Ali, Anthony S. Stein, Casey Brewer, Huafeng Wang, Tinisha McDonaldPiotr Swiderski, Estelle Troadec, Ching Cheng Chen, Adrienne Dorrance, Vinod Pullarkat, Yate Ching Yuan, Danilo Perrotti, Nadia Carlesso, Stephen J. Forman, Marcin Kortylewski, Ya Huei Kuo, Guido Marcucci

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)450-462
Number of pages13
JournalNature Medicine
Volume24
Issue number4
DOIs
StatePublished - May 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    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., ... Marcucci, G. (2018). Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia. Nature Medicine, 24(4), 450-462. https://doi.org/10.1038/nm.4499