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: | Yu-Lin Su, Le Xuan Truong Nguyen, Yuxin Feng, Bin Zhang, Jie Jin, Zhen Chen, Junjing Qiao, Calvin J. Kuo, Matthew Brehove, Huafeng Wang, Danilo Perrotti, Nadia Carlesso, Akihiko Yoshimura, Flavia Pichiorri, Guido Marcucci, Russell C. Rockne, Anjia Han, Ya-Huei Kuo, Ling Li, Tijana Jovanovic-Talisman, Lucy Ghoda, Adrianne Dorrance, David Frankhouser, Anthony S. Stein, Christina Abundis, Yi Zheng, Marcin Kortylewski, Dinh Hoa Hoang, Dandan Zhao, Michael A. Caligiuri |
| المصدر: | Journal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-19 (2021) Journal of Hematology & Oncology |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, medicine.medical_treatment, Vascular permeability, Treatment resistance, Mice, Bone Marrow, hemic and lymphatic diseases, medicine, TNFα, Animals, Humans, Diseases of the blood and blood-forming organs, Molecular Biology, RC254-282, Acute myeloid leukemia, Chemistry, Gene Expression Regulation, Leukemic, Research, Myeloid leukemia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hematology, miR-126, medicine.disease, Up-Regulation, Transplantation, Endothelial stem cell, Mice, Inbred C57BL, Leukemia, Leukemic stem cell, Leukemia, Myeloid, Acute, MicroRNAs, Cytokine, medicine.anatomical_structure, Oncology, fms-Like Tyrosine Kinase 3, Cancer research, Neoplastic Stem Cells, Bone marrow, Stem cell, RC633-647.5, BM vascular niche |
| الوصف: | 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. Graphic abstract |
| تدمد: | 1756-8722 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6adc30c20497ff58ab814ce61f388d46Test https://pubmed.ncbi.nlm.nih.gov/34372909Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6adc30c20497ff58ab814ce61f388d46 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17568722 |
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