Kitada S, Andersen J, Akar S, Zapata J M, Takayama S, Krajewski S, Wang H G, Zhang X, Bullrich F, Croce C M, Rai K, Hines J, Reed J C
Burnham Institute, Cancer Research Center, La Jolla, CA, USA.
Blood. 1998 May 1;91(9):3379-89.
B-cell chronic lymphocytic leukemia (B-CLL) represents a neoplastic disorder caused primarily by defective programmed cell death (PCD), as opposed to increased cell proliferation. Defects in the PCD pathway also contribute to chemoresistance. The expression of several apoptosis-regulating proteins, including the Bcl-2 family proteins Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, and BAD; the Bcl-2-binding protein BAG-1; and the cell death protease Caspase-3 (CPP32), was evaluated by immunoblotting using 58 peripheral blood B-CLL specimens from previously untreated patients. Expression of Bcl-2, Mcl-1, BAG-1, Bax, Bak, and Caspase-3 was commonly found in circulating B-CLL cells, whereas the Bcl-XL and BAD proteins were not present. Higher levels of the anti-apoptotic protein Mcl-1 were strongly correlated with failure to achieve complete remission (CR) after single-agent therapy (fludarabine or chlorambucil) (P = .001), but the presence of only seven CRs among the 42 patients for whom follow-up data were available necessitates cautious interpretation of these observations. Higher levels of the anti-apoptotic protein BAG-1 were also marginally associated with failure to achieve CR (P = .04). Apoptosis-regulating proteins were not associated with patient age, sex, Rai stage, platelet count, hemoglobin (Hb) concentration, or lymph node involvement, although higher levels of Bcl-2 and a high Bcl-2:Bax ratio were correlated with high numbers (>10(5)/microL) of white blood cells (WBC) (P = .01; .007) and higher levels of Bak were weakly associated with loss of allelic heterozygosity at 13q14 (P = .04). On the basis of measurements of apoptosis induction by fludarabine using cultured B-CLL specimens, in vitro chemosensitivity data failed to correlate with in vivo clinical response rates (n = 42) and expression of the various apoptosis-regulating proteins. Although larger prospective studies are required before firm conclusions can be reached, these studies show the expression in B-CLLs of multiple apoptosis-regulating proteins and suggest that the relative levels of some of these, such as Mcl-1, may provide information about in vivo responses to chemotherapy. In vitro chemosensitivity data, however, do not appear to be particularly useful in predicting responses in B-CLL.
B 细胞慢性淋巴细胞白血病（B-CLL）是一种主要由程序性细胞死亡（PCD）缺陷引起的肿瘤性疾病，而非细胞增殖增加所致。PCD 途径的缺陷也会导致化疗耐药。通过免疫印迹法，利用 58 份来自未经治疗患者的外周血 B-CLL 标本，评估了几种凋亡调节蛋白的表达，这些蛋白包括 Bcl-2 家族蛋白 Bcl-2、Bcl-XL、Mcl-1、Bax、Bak 和 BAD；Bcl-2 结合蛋白 BAG-1；以及细胞死亡蛋白酶 Caspase-3（CPP32）。在循环的 B-CLL 细胞中普遍发现 Bcl-2、Mcl-1、BAG-1、Bax、Bak 和 Caspase-3 的表达，而 Bcl-XL 和 BAD 蛋白则不存在。抗凋亡蛋白 Mcl-1 的较高水平与单药治疗（氟达拉滨或苯丁酸氮芥）后未达到完全缓解（CR）密切相关（P = 0.001），但在有随访数据的 42 例患者中仅有 7 例达到 CR，因此对这些观察结果的解读需谨慎。抗凋亡蛋白 BAG-1 的较高水平也与未达到 CR 有轻微关联（P = 0.04）。凋亡调节蛋白与患者年龄、性别、Rai 分期、血小板计数、血红蛋白（Hb）浓度或淋巴结受累情况无关，尽管 Bcl-2 的较高水平和高 Bcl-2:Bax 比值与高白细胞计数（WBC）（>10⁵/μL）相关（P = 0.01；0.007），且 Bak 的较高水平与 13q14 等位基因杂合性缺失有较弱关联（P = 0.04）。基于使用培养的 B-CLL 标本对氟达拉滨诱导凋亡的测量，体外化疗敏感性数据与体内临床反应率（n = 42）以及各种凋亡调节蛋白的表达均无相关性。尽管在得出确切结论之前需要进行更大规模的前瞻性研究，但这些研究显示了多种凋亡调节蛋白在 B-CLL 中的表达，并表明其中一些蛋白的相对水平，如 Mcl-1，可能提供有关体内化疗反应的信息。然而，体外化疗敏感性数据在预测 B-CLL 的反应方面似乎并非特别有用。
