Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27kip1
Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27kip1
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DOI：
10.1182/blood.v98.5.1524
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发表时间：
2001-09-01
期刊：
影响因子：
20.3
通讯作者：
Boussiotis, VA
中科院分区：
文献类型：
--
作者：
Barata, JT;Cardoso, AA;Boussiotis, VA
在正常T细胞发育过程中，白细胞介素-7（IL-7）通过调节未成熟胸腺细胞和成熟T细胞中bcl-2的表达而发挥抗凋亡因子的作用。与正常未成熟胸腺细胞中发生的情况类似，IL-7对前体T细胞急性淋巴细胞白血病（T-ALL）细胞自发凋亡的预防与bcl-2的上调相关。IL-7也与白血病发生有关，因为IL-7转基因小鼠发生淋巴恶性肿瘤，表明IL-7可能调节恶性细胞的产生和扩增。本研究表明，在IL-7存在下，T-ALL细胞不仅上调bcl-2表达和逃避凋亡，而且细胞周期进展，导致cyclin D2和cyclin A的顺序诱导。下调p27（kip 1）是强制性的IL-7介导的细胞周期进程，并在时间上与细胞周期蛋白依赖性激酶（cdk）4和cdk 2的激活和Rb的过度磷酸化相一致。引人注目的是，P27（kip 1）在T-ALL细胞中的强制表达不仅阻止了细胞周期的进展，而且逆转了IL-7介导的bcl-2上调和生存力的提高。这些结果首次表明，IL-7介导的增殖和p27（kip 1）下调之间的因果关系存在于恶性T细胞。此外，这些结果表明，p27（kip 1）可能作为一个肿瘤抑制基因，不仅因为它是一个负调控细胞周期的进展，而且因为它是与诱导原发性恶性细胞的凋亡。(C)2001年，美国血液学会。
In normal T-cell development interleukin-7 (IL-7) functions as an antiapoptotic factor by regulating bcl-2 expression in Immature thymocytes and mature T cells. Similar to what occurs in normal immature thymocytes, prevention of spontaneous apoptosis by IL-7 in precursor T-cell acute lymphoblastic leukemia (T-ALL) cells correlates with up-regulation of bcl-2. IL-7 is also implicated in leukemogenesis because IL-7 transgenic mice develop lymphoid malignancies, suggesting that IL-7 may regulate the generation and expansion of malignant cells. This study shows that in the presence of IL-7, T-ALL cells not only up-regulated bcl-2 expression and escaped apoptosis but also progressed In the cell cycle, resulting in sequential induction of cyclin D2 and cyclin A. Down-regulation of p27(kip1) was mandatory for IL-7-mediated cell cycle progression and temporally coincided with activation of cyclin-dependent kinase (cdk)4 and cdk2 and hyperphosphorylation of Rb. Strikingly, forced expression of P27(kip1) in T-ALL cells not only prevented cell cycle progression but also reversed IL-7-mediated up-regulation of bcl-2 and promotion of viability. These results show for the first time that a causative link between IL-7-mediated proliferation and p27(kip1) down-regulation exists in malignant T cells. Moreover, these results suggest that p27(kip1) may function as a tumor suppressor gene not only because it is a negative regulator of cell cycle progression but also because it Is associated with Induction of apoptosis of primary malignant cells. (C) 2001 by The American Society of Hematology.