Instituto de Investigaciones Hematológicas Mariano R. Castex, Academia Nacional de Medicina de Buenos Aires, Argentina.
Blood Cells Mol Dis. 2010 Oct 15;45(3):192-6. doi: 10.1016/j.bcmd.2010.07.011. Epub 2010 Aug 21.
BCR-ABL fusion gene is implicated in the pathogenesis of chronic myeloid leukemia (CML), encoding the oncoprotein p210(BCR-ABL) with anti-apoptotic activity. The inability to undergo apoptosis is an important mechanism of drug resistance and neoplastic evolution in CML. The gene transcript expression of mitochondrial apoptotic related genes BAX and BCL-XL was evaluated by quantitative Real Time PCR (qPCR) in vitro in K562 cells and in vivo in peripheral blood of 66 CML patients in different stages of the disease: 13 cases at diagnosis, 34 in chronic phase (CP), 10 in accelerated phase (AP) and 9 in blast crisis (BC). Our results in K562 cells showed that all treatments with different tyrosine kinase inhibitors (TKIs) induced a decreased expression of the antiapoptotic oncogene BCL-XL, whereas the proapoptotic gene BAX remains constant with minor modifications. A significantly lower BAX/BCL-XL expression ratio (mean±SEM) than a group of healthy individuals (4.8±0.59) were observed in CML patients at diagnosis (1.28 ± 0.16), in AP (1.14±0.20), in BC (1.16±0.30) and in 18% of cases of patients in CP (2.71±0.40). Most CP cases (82%) showed a significantly increased ratio (10.03±1.30), indicating that the treatment with TKIs efficiently inhibited the expression of BCL-XL by blocking BCR-ABL oncoprotein. The BAX/BCL-XL ratio showed a significant inverse correlation (Spearman P<0.0001) with BCR-ABL/ABL relative expression indicating that low BAX/BCL-XL was associated with disease progression. Accordingly, the follow up of a cohort of eight cases during 6months from diagnosis showed that while the BAX/BCL-XL ratio rapidly increased after treatment in seven cases with good evolution, it decreased in the single case that showed rapid evolution and short survival. Our data suggest that BAX/BCL-XL expression ratio may be a sensitive monitor of disease progression and an early predictor of TKI therapy responsiveness in CML patients.
BCR-ABL 融合基因参与慢性髓性白血病（CML）的发病机制，编码具有抗凋亡活性的癌蛋白 p210(BCR-ABL)。不能发生细胞凋亡是 CML 耐药和肿瘤演变的重要机制。通过实时定量 PCR（qPCR）在体外 K562 细胞中和体内 66 例不同疾病阶段的 CML 患者的外周血中评估线粒体凋亡相关基因 BAX 和 BCL-XL 的基因转录表达：13 例初诊，34 例慢性期（CP），10 例加速期（AP）和 9 例急变期（BC）。我们在 K562 细胞中的结果表明，不同酪氨酸激酶抑制剂（TKI）的所有治疗均诱导抗凋亡癌基因 BCL-XL 的表达降低，而促凋亡基因 BAX 保持不变，仅有微小变化。与一组健康个体（4.8±0.59）相比，CML 患者初诊时（1.28 ± 0.16）、AP 时（1.14±0.20）、BC 时（1.16±0.30）和 CP 中 18%的病例（2.71±0.40）的 BAX/BCL-XL 表达比值明显较低。大多数 CP 病例（82%）显示出明显增加的比值（10.03±1.30），表明 TKI 治疗通过阻断 BCR-ABL 癌蛋白有效抑制了 BCL-XL 的表达。BAX/BCL-XL 比值与 BCR-ABL/ABL 相对表达呈显著负相关（Spearman P<0.0001），表明低 BAX/BCL-XL 与疾病进展相关。因此，对 8 例病例从初诊开始 6 个月的随访显示，在 7 例病情良好的病例中，治疗后 BAX/BCL-XL 比值迅速升高，而在 1 例病情迅速进展和存活时间短的病例中，该比值降低。我们的数据表明，BAX/BCL-XL 表达比值可能是疾病进展的敏感监测指标，也是 CML 患者 TKI 治疗反应的早期预测指标。
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