Schaich M, Illmer T, Seitz G, Mohr B, Schäkel U, Beck J F, Ehninger G
Dept. of Medicine I, University Hospital Carl Gustav Carus, Fetscherstr. 74, 01307 Dresden, Germany.
Haematologica. 2001 May;86(5):470-7.
There is growing evidence that altered expression of genes belonging to the BcL-2 family of apoptosis regulators might influence chemotherapy-induced apoptosis in malignant cells and therefore could confer multidrug resistance. So far expression studies of apoptosis-regulating genes on acute myeloid leukemia (AML) have mainly focused on Bcl-2 itself and most of them have not included other factors involved in drug resistance or apoptosis as parameters determining response to chemotherapy, disease progression and survival.
We therefore examined Bcl-2, Bcl-XL and Bax gene expression in 235 adult patients with de novo or secondary myeloid leukemia. The expression levels were correlated with established prognostic factors such as age, cytogentic aberrations, mdr1 gene expression and clinical outcome in a multivariate analysis.
Bcl-2 and Bcl-XL positive patients had a much lower white blood cell count than negative patients (p<0.001 and p=0.003, respectively). Bcl-2 expression correlated with FAB subtype M0 (p=0.03), Bax with M5b (p=0.02) and Bcl-XL with M6 (p=0.005). Mdr1 expression was more frequently seen in Bcl-2 and Bcl-XL positive patients (p=0.03 and p=0.02, respectively). Remarkably Bax was significantly less frequently expressed in de novo AML patients with high risk cytogenetics (p=0.007). No difference in expression was recognized for Bcl-2 or Bcl-XL when statistical analyses were done for cytogenetic risk groups. However, in the multivariate analysis regarding the group of de novo AML patients < or =60 years with intermediate risk cytogenetics, Bcl-XL expression was found to be an independent negative prognostic factor for response to induction therapy (p=0.04). In contrast, no prognostic impact of Bcl-XL expression on treatment response was seen within the group of patients with high risk cytogenetic findings. Neither Bcl-2 nor Bax nor Bcl-XL expression had a significant influence on overall or disease-free survival.
These data indicate that the prognostic value of Bcl-XL gene expression for treatment response in AML patients < or =60 years is dependent on cytogenetics.
越来越多的证据表明，凋亡调节因子BcL-2家族相关基因表达的改变可能影响恶性细胞化疗诱导的凋亡，因此可能导致多药耐药。到目前为止，急性髓系白血病（AML）凋亡调节基因的表达研究主要集中在Bcl-2本身，并且大多数研究没有将其他与耐药或凋亡相关的因素作为决定化疗反应、疾病进展和生存的参数。
因此，我们检测了235例初发或继发髓系白血病成年患者的Bcl-2、Bcl-XL和Bax基因表达。在多因素分析中，将表达水平与年龄、细胞遗传学异常、mdr1基因表达和临床结局等既定预后因素进行关联分析。
Bcl-2和Bcl-XL阳性患者的白细胞计数远低于阴性患者（分别为p<0.001和p=0.003）。Bcl-2表达与FAB亚型M0相关（p=0.03），Bax与M5b相关（p=0.02），Bcl-XL与M6相关（p=0.005）。Mdr1表达在Bcl-2和Bcl-XL阳性患者中更常见（分别为p=0.03和p=0.02）。值得注意的是，具有高危细胞遗传学特征的初发AML患者中Bax表达明显较少（p=0.007）。对细胞遗传学风险组进行统计分析时，未发现Bcl-2或Bcl-XL表达存在差异。然而，在对年龄≤60岁且细胞遗传学处于中等风险的初发AML患者组进行多因素分析时，发现Bcl-XL表达是诱导治疗反应的独立阴性预后因素（p=0.04）。相比之下，在具有高危细胞遗传学结果的患者组中，未观察到Bcl-XL表达对治疗反应的预后影响。Bcl-2、Bax和Bcl-XL表达对总生存或无病生存均无显著影响。
这些数据表明，Bcl-XL基因表达对年龄≤60岁的AML患者治疗反应的预后价值取决于细胞遗传学。
