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    Treatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AML

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    Author
    Zhang, Bin
    Nguyen, Le Xuan Truong
    Zhao, Dandan
    Frankhouser, David E
    Wang, Huafeng
    Hoang, Dinh Hoa
    Qiao, Junjing
    Abundis, Christina
    Brehove, Matthew
    Su, Yu-Lin
    Feng, Yuxin
    Stein, Anthony
    Ghoda, Lucy
    Dorrance, Adrianne
    Perrotti, Danilo
    Chen, Zhen
    Han, Anjia
    Pichiorri, Flavia
    Jin, Jie
    Jovanovic-Talisman, Tijana
    Caligiuri, Michael A
    Kuo, Calvin J
    Yoshimura, Akihiko
    Li, Ling
    Rockne, Russell C
    Kortylewski, Marcin
    Zheng, Yi
    Carlesso, Nadia
    Kuo, Ya-Huei
    Marcucci, Guido
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    Date
    2021-08-09
    Journal
    Journal of Hematology & Oncology
    Publisher
    Springer Nature
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1186/s13045-021-01133-y
    Abstract
    Background: During acute myeloid leukemia (AML) growth, the bone marrow (BM) niche acquires significant vascular changes that can be offset by therapeutic blast cytoreduction. The molecular mechanisms of this vascular plasticity remain to be fully elucidated. Herein, we report on the changes that occur in the vascular compartment of the FLT3-ITD+ AML BM niche pre and post treatment and their impact on leukemic stem cells (LSCs). Methods: BM vasculature was evaluated in FLT3-ITD+ AML models (MllPTD/WT/Flt3ITD/ITD mouse and patient-derived xenograft) by 3D confocal imaging of long bones, calvarium vascular permeability assays, and flow cytometry analysis. Cytokine levels were measured by Luminex assay and miR-126 levels evaluated by Q-RT-PCR and miRNA staining. Wild-type (wt) and MllPTD/WT/Flt3ITD/ITD mice with endothelial cell (EC) miR-126 knockout or overexpression served as controls. The impact of treatment-induced BM vascular changes on LSC activity was evaluated by secondary transplantation of BM cells after administration of tyrosine kinase inhibitors (TKIs) to MllPTD/WT/Flt3ITD/ITD mice with/without either EC miR-126 KO or co-treatment with tumor necrosis factor alpha (TNFα) or anti-miR-126 miRisten. Results: In the normal BM niche, CD31+Sca-1high ECs lining arterioles have miR-126 levels higher than CD31+Sca-1low ECs lining sinusoids. We noted that during FLT3-ITD+ AML growth, the BM niche lost arterioles and gained sinusoids. These changes were mediated by TNFα, a cytokine produced by AML blasts, which induced EC miR-126 downregulation and caused depletion of CD31+Sca-1high ECs and gain in CD31+Sca-1low ECs. Loss of miR-126high ECs led to a decreased EC miR-126 supply to LSCs, which then entered the cell cycle and promoted leukemia growth. Accordingly, antileukemic treatment with TKI decreased the BM blast-produced TNFα and increased miR-126high ECs and the EC miR-126 supply to LSCs. High miR-126 levels safeguarded LSCs, as shown by more severe disease in secondary transplanted mice. Conversely, EC miR-126 deprivation via genetic or pharmacological EC miR-126 knock-down prevented treatment-induced BM miR-126high EC expansion and in turn LSC protection. Conclusions: Treatment-induced CD31+Sca-1high EC re-vascularization of the leukemic BM niche may represent a LSC extrinsic mechanism of treatment resistance that can be overcome with therapeutic EC miR-126 deprivation.
    Rights/Terms
    © 2021. The Author(s).
    Keyword
    Acute myeloid leukemia
    BM vascular niche
    Leukemic stem cell
    TNFα
    Treatment resistance
    miR-126
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16368
    ae974a485f413a2113503eed53cd6c53
    10.1186/s13045-021-01133-y
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