Chemotherapy-induced niche perturbs hematopoietic reconstitution in B-cell acute lymphoblastic leukemia.
Chemotherapy-induced niche perturbs hematopoietic reconstitution in B-cell acute lymphoblastic leukemia.
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化疗诱导的生态位扰乱 B 细胞急性淋巴细胞白血病的造血重建
DOI：
10.1186/s13046-018-0859-3
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发表时间：
2018-08-29
期刊：
影响因子：
--
通讯作者：
Duan CW
中科院分区：
文献类型：
--
作者：
Tang C;Li MH;Chen YL;Sun HY;Liu SL;Zheng WW;Zhang MY;Li H;Fu W;Zhang WJ;Liang AB;Tang ZH;Hong DL;Zhou BS;Duan CW
研究背景造血干细胞（hematopoietic stem cells，HSCs）在正常骨髓（bone marrow，BM）小生境中维持的分子机制一直是研究的热点。以前，我们证明了化疗诱导的小生境，这是主要由间充质干细胞（MSC），保护残留的B细胞急性淋巴细胞白血病（B-ALL）细胞的化疗药物的侮辱。然而，化疗诱导的小生境对造血干细胞功能在B-ALL中的作用仍不清楚。方法我们建立了致癌性N-MYC驱动的B-ALL小鼠模型，随后用常用化疗药物阿糖胞苷（Ara-C）和柔红霉素（DNR）治疗。处理后，通过免疫荧光染色对BM龛的结构进行成像。通过体外培养和RNA-seq、qRT-PCR检测骨髓间充质干细胞在阿糖胞苷和柔红霉素处理后的自我更新和分化能力。采用系列移植实验检测化疗诱导的小生境对造血干细胞造血重建的影响。流式细胞仪检测HSCs的细胞周期、ROS水平、线粒体膜电位和细胞凋亡。结果化疗诱导的骨髓微环境中的主要成分MSCs自我更新能力下降，易向脂肪细胞和软骨细胞分化。使用RNA-seq的基因表达分析结果显示，MSC具有降低的细胞因子水平，包括SCF、CXCL 12、ANGPT 1、VCAM 1和IL 7。在我们的N-MYC-driven B-ALL小鼠模型中，化疗诱导的骨髓小生境通过促进造血干细胞进入细胞周期，增加细胞内活性氧水平和线粒体膜电位，导致造血干细胞凋亡，从而干扰造血干细胞的造血重建。
BackgroundConsiderable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear.MethodsWe established an oncogenicN-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry.ResultsThe MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in ourN-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs.ConclusionsChemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.
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64.5
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50.3
作者：
Duan, Cai-Wen;Shi, Jun;Hong, Deng-Li
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