Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with Bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia
Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with Bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia
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DOI：
10.1182/blood.v96.1.297.013k24_297_306
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发表时间：
2000-07-01
期刊：
影响因子：
20.3
通讯作者：
Ludwig, WD
中科院分区：
文献类型：
--
作者：
Karawajew, L;Ruppert, V;Ludwig, WD
在正常的T细胞发育过程中，IL-7作为一种非多余的抗凋亡因子，通过调节前T细胞中Bcl2的表达而发挥作用。在本研究中，我们探讨了IL-7及相关细胞因子作为凋亡调节因子在前体T细胞急性淋巴细胞白血病(T-ALL)中的作用。为此，我们前瞻性地研究了T-ALL患儿的白血病细胞对IL-7、IL-4和IL-2的反应性(通过流式细胞仪评估)，细胞因子受体的表达谱，以及Bcl2和Bax蛋白的表达水平。IL-7比IL-4和IL-2更有效地抑制细胞的凋亡，其作用与IL-7Rα链的表达水平和Bcl2蛋白的表达上调有关(P<；.0001)。根据T-ALL样本的体外IL-7反应对其进行细分，发现IL-7难治性样本CD34(P<；.0001)和髓系相关抗原CD34(P=.01)的阳性率更高，而IL-7的反应性与更成熟的分化相关T细胞抗原(CD1a，表面CD3，CD4/8；P<；0.05)的表达有关。此外，IL-7在体外抑制细胞凋亡的程度与早期细胞减少有定量关系，如第8天的强的松外周血反应和第15天的骨髓细胞减少(n=87；P<；0.05)。多因素分析显示，只有IL-7的反应性对T-ALL早期细胞减少有独立的影响(P<；0.05)，因此IL-7的敏感性可能与T-ALL的预后相关。(血。2000；96：297-306)(C)2000由美国血液病学会提供。
In normal T-cell development, IL-7 plays a nonredundant role as an antiapoptic factor by regulating Bcl-2 expression in pro-T cells. In the current study, we addressed the roles of IL-7 and related cytokines as apoptosis modulating factors in precursor T-cell acute lymphoblastic leukemia (T-ALL). To this end, leukemic blasts from pediatric patients with T-ALL were prospectively investigated as to their responsiveness to IL-7, IL-4, and IL-2 (in terms of modulation of spontaneous apoptosis, assessed by flow cytometry), cytokine receptor expression profiles, and expression levels of Bcl-2 and Bax proteins. IL-7, in contrast to IL-4 and IL-2, was highly efficient in apoptosis Inhibition, and this effect correlated with the expression levels of IL-7R alpha chain and with the up-regulation of Bcl-2 protein expression (P < .0001). Subclassification of T-ALL samples (n = 130) according to their in vitro IL-7 responses revealed that IL-7 refractory samples were more frequently positive for CD34 (P < .0001) and the myeloid-associated antigen CD34 (P = .01), whereas IL-7 responsiveness was associated with an expression of more mature differentiation-associated T-cell antigens (CD1a, surface CD3, CD4/8; P < .05). Furthermore, the extent of apoptosis inhibition by IL-7 in vitro quantitatively correlated with early cytoreduction as determined by the prednisone peripheral blood response on day 8 and cytoreduction in the marrow on day 15 (n = 87; P < .05). Multivariate analysis of the apoptosis-related parameters investigated, in eluding spontaneous apoptosis, its inhibition by IL-7, and expression levels of Bcl-2 and Bax, showed that only IL-7 responsiveness has an independent impact on early cytoreduction (P < .05), thus indicating a potential prognostic relevance of IL-7 sensitivity in T-ALL. (Blood. 2000;96:297-306) (C) 2000 by The American Society of Hematology.