Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress
Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress
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DOI：
10.1182/blood.2019001398
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发表时间：
2019-10-24
期刊：
影响因子：
20.3
通讯作者：
Fielding, Adele K.
中科院分区：
文献类型：
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作者：
Burt, Richard;Dey, Aditi;Fielding, Adele K.
我们研究并模拟了成人急性淋巴细胞白血病（ALL）中的间充质基质细胞（MSC）生态位。我们使用基因表达谱，细胞因子/趋化因子定量，流式细胞术，和各种成像技术，以显示间充质干细胞，直接从原发性急性淋巴细胞白血病患者的骨髓标本分离，经常采用活化，癌症相关的成纤维细胞表型。当暴露于活性氧（ROS）诱导化疗剂阿糖胞苷（AraC）和柔红霉素（DNR）时，正常的原代人MSC和MSC细胞系HS 27 a都被从头激活，这一现象被抗氧化剂N-乙酰半胱氨酸阻断。在具有ALL靶标的共培养模型中对化疗活化的HS 27 a细胞进行功能性评价。活化的MSC通过隧道纳米管（TNT）的线粒体转移防止ALL靶点中治疗诱导的凋亡和死亡。通过选择性线粒体耗竭或微管抑制剂（如长春新碱（VCR））干扰TNT形成来减少线粒体转移，阻止了活化MSC的“拯救”功能。皮质类固醇，也是ALL治疗的主要手段，阻止了MSC的激活。我们还证明了AraC（而不是VCR）在播散性SEM细胞源性ALL的小鼠NSG模型中诱导MSC活化、线粒体转移和线粒体质量增加，其中AraC后CD 19（+）细胞与巢蛋白（+）MSC密切相关，但在其他条件下不诱导。我们的数据提出了一个易于临床开发的机制，以改善治疗急性淋巴细胞白血病，其中传统的ROS诱导化疗往往是无效的，在根除残留疾病，尽管有效地杀死了大部分人口。
We investigated and modeled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukemia (ALL). We used gene expression profiling, cytokine/chemokine quantification, flow cytometry, and a variety of imaging techniques to show that MSCs, directly isolated from the primary bone marrow specimens of patients with ALL, frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, primary human MSCs and the MSC cell line HS27a both were activated de novo, when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) and daunorubicin (DNR), a phenomenon blocked by the antioxidant N-acetyl cysteine. Chemotherapy-activated HS27a cells were functionally evaluated in a coculture model with ALL targets. Activated MSCs prevented therapy-induced apoptosis and death in ALL targets, via mitochondrial transfer through tunneling nanotubes (TNTs). Reduction of mitochondrial transfer by selective mitochondrial depletion or interference with TNT formation by microtubule inhibitors, such as vincristine (VCR), prevented the "rescue" function of activated MSCs. Corticosteroids, also a mainstay of ALL therapy, prevented the activation of MSCs. We also demonstrated that AraC (but not VCR) induced activation of MSCs, mitochondrial transfer, and mitochondrial mass increase in a murine NSG model of disseminated SEM cell-derived ALL, wherein CD19(+) cells closely associated with nestin(+) MSCs after AraC, but not in the other conditions. Our data propose a readily clinically exploitable mechanism for improving treatment of ALL, in which traditional ROS-inducing chemotherapies are often ineffective at eradicating residual disease, despite efficiently killing the bulk population.