Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer. 2012 Feb 15;118(4):1023-31. doi: 10.1002/cncr.26360. Epub 2011 Jul 14.
Despite the high complete response rates achieved with fludarabine-based regimens, relapse is inevitable in chronic lymphocytic leukemia (CLL). Relapsed patients often acquire deletions of the short arm of chromosome 17 (del[17p]), which are closely associated with tumor protein 53 (TP53) mutations. Wild-type p53 up-regulates and activates B-cell CLL/lymphoma 2 (BCL-2)-associated X protein (BAX), and it down-regulates and inactivates BCL-2. The small-molecule BCL-2 inhibitor ABT-737 induces apoptosis in a BAX-dependent and BCL-2 homologous antagonist-killer (BAK)-dependent manner. The role of p53 in sensitivity of CLL cells to BCL-2 inhibition has not been extensively investigated.
The authors investigated the association of del(17p) with ABT-737 sensitivity in CLL cells from 50 patients. Stable p53 and BAX knockdown cells were used for mechanistic studies.
CLL cells with del(17p) were less sensitive to ABT-737-induced BAX activation and apoptosis than CLL cells without del(17p) (39% ± 7.3% vs 63.7% ± 2.9% [specific annexin V induction]; P < .01). A positive correlation between the degrees of apoptosis induced by ABT-737 and by the p53-activating binding protein homolog murine double minute (MDM2) antagonist nutlin-3a (correlation coefficient [r] = 0.75; P < .0001) was observed. CLL cells with del(17p) expressed lower levels of BAX than those without del(17p) (0.67 ± 0.12 vs 1.27 ± 0.10 in relative protein expression levels; P < .01). Knockdown of p53 or BAX in leukemia cells resulted in decreased apoptosis induced by ABT-737.
The current data indicated that p53 dysfunction may lead to decreased apoptosis induction by ABT-737.
尽管基于氟达拉滨的方案实现了很高的完全缓解率，但慢性淋巴细胞白血病（CLL）的复发是不可避免的。复发患者常发生 17 号染色体短臂缺失（del[17p]），这与肿瘤蛋白 53（TP53）突变密切相关。野生型 p53 上调并激活 B 细胞 CLL/淋巴瘤 2（BCL-2）相关 X 蛋白（BAX），并下调和失活 BCL-2。小分子 BCL-2 抑制剂 ABT-737 以 BAX 依赖性和 BCL-2 同源拮抗剂杀伤（BAK）依赖性方式诱导细胞凋亡。p53 在 CLL 细胞对 BCL-2 抑制的敏感性中的作用尚未得到广泛研究。
作者研究了 50 例患者的 CLL 细胞中 del(17p)与 ABT-737 敏感性的相关性。使用稳定的 p53 和 BAX 敲低细胞进行机制研究。
del(17p)的 CLL 细胞对 ABT-737 诱导的 BAX 激活和凋亡的敏感性低于无 del(17p)的 CLL 细胞（特异性 Annexin V 诱导的 39%±7.3%与 63.7%±2.9%[P<.01]）。ABT-737 诱导凋亡的程度与 p53 激活结合蛋白同源物鼠双微体（MDM2）拮抗剂 nutlin-3a 诱导凋亡的程度呈正相关（相关系数[r]=0.75；P<.0001）。del(17p)的 CLL 细胞表达的 BAX 水平低于无 del(17p)的 CLL 细胞（相对蛋白表达水平的 0.67±0.12 与 1.27±0.10[P<.01]）。白血病细胞中 p53 或 BAX 的敲低导致 ABT-737 诱导的凋亡减少。
目前的数据表明，p53 功能障碍可能导致 ABT-737 诱导的凋亡减少。
