Department of Evolutionary Biology, University of Siena, 53100 Siena, Italy.
Blood. 2010 May 6;115(18):3726-36. doi: 10.1182/blood-2009-08-239244. Epub 2010 Jan 8.
Intrinsic apoptosis defects underlie to a large extent the extended survival of malignant B cells in chronic lymphocytic leukemia (CLL). Here, we show that the Shc family adapter p66Shc uncouples the B-cell receptor (BCR) from the Erk- and Akt-dependent survival pathways, thereby enhancing B-cell apoptosis. p66Shc expression was found to be profoundly impaired in CLL B cells compared with normal peripheral B cells. Moreover, significant differences in p66Shc expression were observed in patients with favorable or unfavorable prognosis, based on the mutational status of IGHV genes, with the lowest expression in the unfavorable prognosis group. Analysis of the expression of genes implicated in apoptosis defects of CLL showed an alteration in the balance of proapoptotic and antiapoptotic members of the Bcl-2 family in patients with CLL. Reconstitution experiments in CLL B cells, together with data obtained on B cells from p66Shc(-/-) mice, showed that p66Shc expression correlates with a bias in the Bcl-2 family toward proapoptotic members. The data identify p66Shc as a novel regulator of B-cell apoptosis which attenuates BCR-dependent survival signals and modulates Bcl-2 family expression. They moreover provide evidence that the p66Shc expression defect in CLL B cells may be causal to the imbalance toward the antiapoptotic Bcl-2 family members in these cells.
内在凋亡缺陷在很大程度上是慢性淋巴细胞白血病 (CLL) 中恶性 B 细胞存活时间延长的基础。在这里，我们表明 Shc 家族衔接蛋白 p66Shc 将 B 细胞受体 (BCR) 与 Erk 和 Akt 依赖性存活途径解偶联，从而增强 B 细胞凋亡。与正常外周 B 细胞相比，CLL B 细胞中的 p66Shc 表达明显受损。此外，根据 IGHV 基因的突变状态，在具有有利或不利预后的患者中观察到 p66Shc 表达的显着差异，在不利预后组中表达最低。对涉及 CLL 凋亡缺陷的基因表达的分析表明，CLL 患者中促凋亡和抗凋亡 Bcl-2 家族成员的平衡发生改变。在 CLL B 细胞中的重建实验以及 p66Shc(-/-) 小鼠的 B 细胞获得的数据表明，p66Shc 的表达与 Bcl-2 家族向促凋亡成员的倾斜相关。这些数据确定了 p66Shc 是 B 细胞凋亡的新调节剂，可减弱 BCR 依赖性存活信号并调节 Bcl-2 家族的表达。此外，它们提供的证据表明，CLL B 细胞中的 p66Shc 表达缺陷可能是这些细胞中抗凋亡 Bcl-2 家族成员失衡的原因。
