Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen.
Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen.
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Notch1 诱导的 T 细胞白血病可通过脾脏中的微环境信号而增强。
DOI：
10.1186/s13045-014-0071-7
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发表时间：
2014-11-04
影响因子：
28.5
通讯作者：
Zheng G
中科院分区：
文献类型：
--
作者：
Ma S;Shi Y;Pang Y;Dong F;Cheng H;Hao S;Xu J;Zhu X;Yuan W;Cheng T;Zheng G
白血病是一种起源于造血细胞的系统性恶性肿瘤。细胞外环境对白血病细胞的生存、增殖和播散有重要影响。脾脏是髓外造血的重要器官，也是淋巴系统恶性肿瘤常见的浸润部位。脾肿大常见于T细胞急性淋巴细胞白血病（T-ALL），与预后不良有关。然而，脾脏微环境如何明显影响T-ALL细胞，而不是骨髓（BM）微环境尚未解决。本研究采用Notch 1诱导的小鼠T-ALL模型。采用流式细胞术和双光子荧光显微镜分析T-ALL细胞的早期分布。进行MILLIPLEX® MAP多重免疫测定以测量不同微环境中的细胞因子/趋化因子水平。采用体外Transwell实验和共培养实验检测脾微环境的影响。进行脾切除术以评估器官特异性对携带T-ALL的小鼠的存活的影响。流式细胞术和双光子荧光显微镜分析显示，注射T-ALL细胞后，脾脏中的白血病细胞比骨髓中的白血病细胞多。通过筛选一组细胞因子/趋化因子，发现MIP-3β在脾脏微环境中的水平高于BM微环境。体外transwell实验进一步证实MIP-3β可募集高表达MIP-3β受体CCR 7的T-ALL细胞。此外，脾脏微环境刺激T-ALL细胞表达更高水平的MIP-3β，这进一步将T-ALL细胞募集到脾脏。共培养实验发现脾脏微环境比骨髓更能刺激T-ALL细胞的增殖和迁移。此外，从脾脏移植T-ALL细胞的小鼠的寿命比从BM移植的小鼠的寿命短，这表明脾脏微环境诱导的T-ALL细胞的效力增加。此外，脾切除术延长了白血病小鼠的生存期。我们的研究证明了对白血病发展的器官特异性影响。具体而言，T-ALL细胞可以通过脾脏微环境增强，因此脾脏可以作为治疗某些类型白血病的靶器官。本文的在线版本（doi：10.1186/s13045-014-0071-7）包含补充材料，可供授权用户使用。
Leukemia is a systemic malignancy originated from hematopoietic cells. The extracellular environment has great impacts on the survival, proliferation and dissemination of leukemia cells. The spleen is an important organ for extramedullary hematopoiesis and a common infiltration site in lymphoid malignancies. Splenomegaly, frequently observed in T cell acute lymphoblastic leukemia (T-ALL), is associated with poor prognosis. However, how the spleen microenvironment distinctly affects T-ALL cells as opposed to bone marrow (BM) microenvironment has not been addressed. A Notch1-induced mouse T-ALL model was applied in this study. Flow cytometry and two-photon fluorescence microscopy were used to analyze early distribution of T-ALL cells. MILLIPLEX® MAP Multiplex Immunoassay was performed to measure cytokine/chemokine levels in different microenvironments. Transwell and co-culture experiments were used to test the effects of splenic microenvironment in vitro. Splenectomy was performed to assess the organ specific impact on the survival of T-ALL-bearing mice. More leukemia cells were detected in the spleen than in the BM after injection of T-ALL cells by flow cytometry and two-photon fluorescence microscopy analysis. By screening a panel of cytokines/chemokines, a higher level of MIP-3β was found in the splenic microenvironment than BM microenvironment. In vitro transwell experiment further confirmed that MIP-3β recruits T-ALL cells which express a high level of MIP-3β receptor, CCR7. Furthermore, the splenic microenvironment stimulates T-ALL cells to express a higher level of MIP-3β, which further recruits T-ALL cells to the spleen. Co-culture experiment found that the splenic microenvironment more potently stimulated the proliferation and migration of T-ALL cells than BM. Moreover, the mice transplanted with T-ALL cells from the spleen had a shorter life span than those transplanted from BM, suggesting increased potency of the T-ALL cells induced by the splenic microenvironment. In addition, splenectomy prolonged the survival of leukemic mice. Our study demonstrates an organ specific effect on leukemia development. Specifically, T-ALL cells can be potentiated by splenic microenvironment and thus spleen may serve as a target organ for the treatment of some types of leukemia. The online version of this article (doi:10.1186/s13045-014-0071-7) contains supplementary material, which is available to authorized users.
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影响因子：
37.3
作者：
Catusse J;Leick M;Groch M;Clark DJ;Buchner MV;Zirlik K;Burger M
通讯作者：
Burger M
影响因子：
64.5
作者：
Hu B;Castillo E;Harewood L;Ostano P;Reymond A;Dummer R;Raffoul W;Hoetzenecker W;Hofbauer GF;Dotto GP
通讯作者：
Dotto GP
DOI：
10.1038/nrm3112
发表时间：
2011-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1038/nri3132
发表时间：
2011-12-23
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.7
作者：
Corcione, A;Arduino, N;Pistoia, V
通讯作者：
Pistoia, V