Treatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AML.
Treatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AML.
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治疗诱导的小动脉血运重建和骨髓微环境中 miR-126 的增强可保护 AML 中的白血病干细胞
DOI：
10.1186/s13045-021-01133-y
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发表时间：
2021-08-09
影响因子：
28.5
通讯作者：
Marcucci G
中科院分区：
文献类型：
--
作者：
Zhang B;Nguyen LXT;Zhao D;Frankhouser DE;Wang H;Hoang DH;Qiao J;Abundis C;Brehove M;Su YL;Feng Y;Stein A;Ghoda L;Dorrance A;Perrotti D;Chen Z;Han A;Pichiorri F;Jin J;Jovanovic-Talisman T;Caligiuri MA;Kuo CJ;Yoshimura A;Li L;Rockne RC;Kortylewski M;Zheng Y;Carlesso N;Kuo YH;Marcucci G
背景在急性髓系白血病（AML）的生长过程中，骨髓（BM）小生境获得了显著的血管变化，这种变化可以通过治疗性母细胞减少来抵消。这种血管可塑性的分子机制仍有待充分阐明。在此，我们报告的变化，发生在血管区室的FLT 3-ITD+ AML BM龛治疗前和治疗后，他们对白血病干细胞（LSCs）的影响。MethodsBM脉管系统进行了评估FLT 3-ITD+ AML模型（MIIPTD/WT/Flt 3 ITD/小鼠和患者衍生的异种移植物）的长骨，颅骨血管通透性测定，和流式细胞术分析的三维共聚焦成像。通过Luminex测定法测量细胞因子水平，并通过Q-RT-PCR和miRNA染色评估miR-126水平。内皮细胞（EC）miR-126敲除或过表达的野生型（wt）和MllPTD/WT/Flt 3 ITD/ITD小鼠作为对照。通过在向具有/不具有EC miR-126 KO或与肿瘤坏死因子α（TNFα）或抗miR-126 miRisten共治疗的MllPTD/WT/Flt 3 ITD/ITD小鼠施用酪氨酸激酶抑制剂（TKI）后进行BM细胞的二次移植来评估治疗诱导的BM血管变化对LSC活性的影响。小动脉衬里的CD 31 +Sca-1highEC的miR-126水平高于窦状隙衬里的CD 31 +Sca-1 lowEC。我们注意到，在FLT 3-ITD+ AML生长期间，BM龛失去小动脉并获得血窦。这些变化由TNFα介导，TNF α是AML原始细胞产生的细胞因子，可诱导EC miR-126下调，并导致CD 31 +Sca-1highEC耗竭和CD 31 +Sca-1 lowEC增加。miR-126 highEC的缺失导致EC向LSC供应的miR-126减少，然后LSC进入细胞周期并促进白血病生长。因此，TKI抗白血病治疗降低了BM原始细胞产生的TNFα，增加了miR-126 highEC和EC miR-126向LSC的供应。高miR-126水平保护了LSC，如二次移植小鼠中更严重的疾病所示。相反，通过遗传或药理学EC miR-126敲低的EC miR-126剥夺阻止了治疗诱导的BM miR-126 highEC扩增，进而阻止了LSC protection.ConclusionsTreatment-induced CD 31 +Sca-1highEC re-vascularization of the leukemic BM niche可能代表了治疗抗性的LSC外在机制，可以通过治疗性EC miR-126剥夺来克服。
BackgroundDuring 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).MethodsBM vasculature was evaluated in FLT3-ITD+ AML models (MllPTD/WT/Flt3ITD/ITDmouse 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) andMllPTD/WT/Flt3ITD/ITDmice 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) toMllPTD/WT/Flt3ITD/ITDmice with/without either EC miR-126 KO or co-treatment with tumor necrosis factor alpha (TNFα) or anti-miR-126 miRisten.ResultsIn the normal BM niche, CD31+Sca-1highECs lining arterioles have miR-126 levels higher than CD31+Sca-1lowECs 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-1highECs and gain in CD31+Sca-1lowECs. Loss of miR-126highECs 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-126highECs 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-126highEC expansion and in turn LSC protection.ConclusionsTreatment-induced CD31+Sca-1highEC 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
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影响因子：
3.7
作者：
Le Bras A;Samson C;Trentini M;Caetano B;Lelievre E;Mattot V;Beermann F;Soncin F
通讯作者：
Soncin F
影响因子：
4.6
作者：
Egawa, Gyohei;Nakamizo, Satoshi;Natsuaki, Yohei;Doi, Hiromi;Miyachi, Yoshiki;Kabashima, Kenji
通讯作者：
Kabashima, Kenji
SPRSED-1负调节过敏原诱导的气道嗜酸性粒细胞和反应性过高。
影响因子：
15.3
作者：
Inoue, H;Kato, R;Fukuyama, S;Nonami, A;Taniguchi, KI;Matsunmoto, K;Nakano, T;Tsuda, M;Matsumura, M;Kubo, M;Ishikawa, F;Moon, BG;Takatsu, K;Nakanishi, Y;Yoshimura, A
通讯作者：
Yoshimura, A
影响因子：
23.9
作者：
Duarte D;Hawkins ED;Akinduro O;Ang H;De Filippo K;Kong IY;Haltalli M;Ruivo N;Straszkowski L;Vervoort SJ;McLean C;Weber TS;Khorshed R;Pirillo C;Wei A;Ramasamy SK;Kusumbe AP;Duffy K;Adams RH;Purton LE;Carlin LM;Lo Celso C
通讯作者：
Lo Celso C
影响因子：
14.8
作者：
Kusumbe，Anjali P.;Ramasamy，Saravana K.;Adams，Ralf H.
通讯作者：
Adams，Ralf H.