Show simple item record

dc.contributor.authorZhang, Bin
dc.contributor.authorNguyen, Le Xuan Truong
dc.contributor.authorZhao, Dandan
dc.contributor.authorFrankhouser, David E
dc.contributor.authorWang, Huafeng
dc.contributor.authorHoang, Dinh Hoa
dc.contributor.authorQiao, Junjing
dc.contributor.authorAbundis, Christina
dc.contributor.authorBrehove, Matthew
dc.contributor.authorSu, Yu-Lin
dc.contributor.authorFeng, Yuxin
dc.contributor.authorStein, Anthony
dc.contributor.authorGhoda, Lucy
dc.contributor.authorDorrance, Adrianne
dc.contributor.authorPerrotti, Danilo
dc.contributor.authorChen, Zhen
dc.contributor.authorHan, Anjia
dc.contributor.authorPichiorri, Flavia
dc.contributor.authorJin, Jie
dc.contributor.authorJovanovic-Talisman, Tijana
dc.contributor.authorCaligiuri, Michael A
dc.contributor.authorKuo, Calvin J
dc.contributor.authorYoshimura, Akihiko
dc.contributor.authorLi, Ling
dc.contributor.authorRockne, Russell C
dc.contributor.authorKortylewski, Marcin
dc.contributor.authorZheng, Yi
dc.contributor.authorCarlesso, Nadia
dc.contributor.authorKuo, Ya-Huei
dc.contributor.authorMarcucci, Guido
dc.date.accessioned2021-08-12T12:24:29Z
dc.date.available2021-08-12T12:24:29Z
dc.date.issued2021-08-09
dc.identifier.urihttp://hdl.handle.net/10713/16368
dc.description.abstractBackground: 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.en_US
dc.description.urihttps://doi.org/10.1186/s13045-021-01133-yen_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofJournal of Hematology & Oncologyen_US
dc.rights© 2021. The Author(s).en_US
dc.subjectAcute myeloid leukemiaen_US
dc.subjectBM vascular nicheen_US
dc.subjectLeukemic stem cellen_US
dc.subjectTNFαen_US
dc.subjectTreatment resistanceen_US
dc.subjectmiR-126en_US
dc.titleTreatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AMLen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s13045-021-01133-y
dc.identifier.pmid34372909
dc.source.volume14
dc.source.issue1
dc.source.beginpage122
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland


This item appears in the following Collection(s)

Show simple item record