دورية أكاديمية
Treatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AML
| العنوان: | Treatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AML |
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| المؤلفون: | Bin Zhang, Le Xuan Truong Nguyen, Dandan Zhao, David E. Frankhouser, Huafeng Wang, Dinh Hoa Hoang, Junjing Qiao, Christina Abundis, Matthew Brehove, Yu-Lin Su, Yuxin Feng, Anthony Stein, Lucy Ghoda, Adrianne Dorrance, Danilo Perrotti, Zhen Chen, Anjia Han, Flavia Pichiorri, Jie Jin, Tijana Jovanovic-Talisman, Michael A. Caligiuri, Calvin J. Kuo, Akihiko Yoshimura, Ling Li, Russell C. Rockne, Marcin Kortylewski, Yi Zheng, Nadia Carlesso, Ya-Huei Kuo, Guido Marcucci |
| المصدر: | Journal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-19 (2021) |
| بيانات النشر: | BMC, 2021. |
| سنة النشر: | 2021 |
| المجموعة: | LCC:Diseases of the blood and blood-forming organs LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: | Acute myeloid leukemia, BM vascular niche, TNFα, miR-126, Leukemic stem cell, Treatment resistance, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | 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 (Mll PTD/WT/Flt3 ITD/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 Mll PTD/WT/Flt3 ITD/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 Mll PTD/WT/Flt3 ITD/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. Graphic abstract |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1756-8722 |
| العلاقة: | https://doaj.org/toc/1756-8722Test |
| DOI: | 10.1186/s13045-021-01133-y |
| الوصول الحر: | https://doaj.org/article/52f9905cc5f14aa08a70fe465bcdd2b1Test |
| رقم الانضمام: | edsdoj.52f9905cc5f14aa08a70fe465bcdd2b1 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17568722 |
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| DOI: | 10.1186/s13045-021-01133-y |