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

Nature Medicine volume 24, pages 450–462 (2018)Cite this article

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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.

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Figure 1: Human and mouse CML LSCs express the highest levels of miR-126 among CML subpopulations.
Figure 2: BCR–ABL downregulates miR-126 expression in CML cells.
Figure 3: BCR–ABL deregulates miR-126 biogenesis.
Figure 4: Endothelial cells in the niche supply miR-126 to normal and CML LT-HSCs.
Figure 5: Endothelial cells in the BM niche supply miR-126 to CML LT-HSCs.
Figure 6: Knockdown of miR-126 expression by lentiviruses or the CpG–miR-126 inhibitor in combination with nilotinib enhances the in vivo targeting of CML LSCs.

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Acknowledgements

We acknowledge the support of the Animal Resources Center, Analytical Cytometry, Pathology (Liquid Tumor), Bioinformatics, Electron Microscopy, Light Microscopy, Integrative Genomics and DNA/RNA Cores at City of Hope (COH) Comprehensive Cancer Center, which is supported by the National Cancer Institute (NCI) of the US National Institutes of Health (NIH) under award number P30CA33572. We thank C.J. Kuo (Stanford University) for the Mir126aflox/flox mice and are grateful to the COH Comprehensive Cancer Center, the Glasgow Experimental Cancer Medicine Centre and the SPIRIT trials, together with the patients and their physicians, for providing primary patient material for this study. This work was supported in part by NCI grants CA205247 (Y.-H.K.), CA102031 (G.M.), CA201184 (G.M.), CA213131 (M.K.), CA180861 (G.M.), CA158350 (G.M.), CA163800 (P.D.), and CA184411 (L.L.), the Gehr Family Foundation (G.M.), the George Hoag Family Foundation (G.M.), Cancer Research UK program grant C11074/A11008 (T.L.H.) and The Howat Foundation (T.L.H.).

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Author notes

  1. Bin Zhang and Le Xuan Truong Nguyen: These authors contributed equally to this work.

  2. Marcin Kortylewski, Ya-Huei Kuo and Guido Marcucci: These jointly directed this work.

Authors and Affiliations

  1. Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope Medical Center, Duarte, California, USA

    Bin Zhang, Le Xuan Truong Nguyen, Ling Li, Dandan Zhao, Bijender Kumar, Herman Wu, Allen Lin, David S Snyder, Haris Ali, Anthony S Stein, Casey Brewer, Huafeng Wang, Tinisha McDonald, Piotr Swiderski, Estelle Troadec, Ching-Cheng Chen, Vinod Pullarkat, Yate-Ching Yuan, Nadia Carlesso, Stephen J Forman, Ya-Huei Kuo & Guido Marcucci

  2. Department of Medical Biotechnology, Biotechnology Center of Ho Chi Minh City, Ho Chi Minh City, Viet Nam

    Le Xuan Truong Nguyen

  3. Paul O' Gorman Leukemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    Francesca Pellicano, Lisa Hopcroft, Mhairi Copland & Tessa L Holyoake

  4. Department of Immuno-oncology, City of Hope Medical Center, Duarte, California, USA

    Yu-Lin Su & Marcin Kortylewski

  5. Stanford University School of Medicine, Stanford, California, USA

    Calvin J Kuo

  6. University of Alabama at Birmingham, Birmingham, Alabama, USA

    Ravi Bhatia

  7. Department of Hematology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Huafeng Wang

  8. Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA

    Adrienne Dorrance

  9. Department of Medicine, Biochemistry and Molecular Biology and the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine Baltimore, Baltimore, Maryland, USA

    Danilo Perrotti

  10. Deparment of Hematology, Hammersmith Hospital, Imperial College London, London, UK

    Danilo Perrotti

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  1. Bin Zhang
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Contributions

B.Z. and L.X.T.N. designed and conducted experiments, analyzed data and wrote the manuscript; L.L., D.Z., B.K., H. Wu, F.P., Y.-L.S., C.B., H. Wang, T.M. and E.T. conducted experiments; A.L., D.S.S., H.A. and A.S.S. provided samples and reviewed the patients' data; P.S. and M.K. designed the CpG–miR-126 inhibitor and reviewed data and the manuscript; L.H., C.-C.C., A.D., V.P., Y.-C.Y., D.P. and N.C. analyzed data; C.J.K. provided the miR-126 c-KO mouse model; R.B. provided the B6 SCLtTA×BCR–ABL mouse model of CML; M.C., T.L.H. and S.J.F. provided patient samples, designed experiments and reviewed the manuscript; M.K. and Y.-H.K. designed experiments, analyzed data and reviewed the manuscript; G.M. designed experiments, analyzed data, wrote the manuscript and provided administrative support.

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Correspondence to Bin Zhang or Guido Marcucci.

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Zhang, B., Nguyen, L., Li, L. et al. Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia. Nat Med 24, 450–462 (2018). https://doi.org/10.1038/nm.4499

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