Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses.
Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses.
复制标题
DOI：
10.1182/blood.v91.9.3379.3379_3379_3389
复制
发表时间：
1998-05
期刊：
影响因子：
20.3
通讯作者：
S. Kitada;J. Andersen;S. Akar;J. Zapata;S. Takayama;S. Krajewski;H. G. Wang;X. Zhang;F. Bullrich-F.
中科院分区：
文献类型：
--
作者：
S. Kitada;J. Andersen;S. Akar;J. Zapata;S. Takayama;S. Krajewski;H. G. Wang;X. Zhang;F. Bullrich-F.
B细胞慢性淋巴细胞白血病（B-CLL）是一种主要由缺陷性程序性细胞死亡（PCD）引起的肿瘤性疾病，与细胞增殖增加相反。PCD途径中的缺陷也有助于化学抗性。使用来自先前未治疗患者的58个外周血B-CLL标本，通过免疫印迹法评估几种凋亡调节蛋白的表达，包括Bcl-2家族蛋白Bcl-2、Bcl-XL、Mcl-1、Bax、巴克和BAD; Bcl-2结合蛋白BAG-1;和细胞死亡蛋白酶Caspase-3（CPP 32）。Bcl-2、Mcl-1、BAG-1、Bax、巴克和半胱天冬酶-3的表达在循环B-CLL细胞中常见，而Bcl-XL和BAD蛋白不存在。较高水平的抗凋亡蛋白Mcl-1与单药治疗（氟达拉滨或苯丁酸氮芥）后未能达到完全缓解（CR）密切相关（P = 0.001），但在42例随访数据可用的患者中，仅7例CR的存在需要对这些观察结果进行谨慎解释。较高水平的抗凋亡蛋白BAG-1也与未能达到CR轻微相关（P = 0.04）。凋亡调节蛋白与患者年龄、性别、Rai分期、血小板计数、血红蛋白浓度或淋巴结受累无关，尽管较高水平的Bcl-2和较高的Bcl-2：Bax比值与高数量（>10（5）/μ L）的白色血细胞（WBC）相关（P = 0.01; 0.007），较高水平的巴克与13 q14等位基因杂合性丢失弱相关（P = 0.04）。氟达拉滨诱导细胞凋亡的测量的基础上，使用培养的B-CLL标本，在体外化疗敏感性数据未能与体内临床反应率（n = 42）和各种凋亡调节蛋白的表达。虽然在得出确切的结论之前需要更大规模的前瞻性研究，但这些研究显示了多种增殖调节蛋白在B-CLL中的表达，并表明其中一些蛋白（如Mcl-1）的相对水平可能提供有关体内对化疗反应的信息。然而，体外化疗敏感性数据在预测B-CLL的反应方面似乎并不特别有用。
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.