Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML)
Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML)
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DOI：
10.1182/blood-2002-06-1714
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发表时间：
2003-03-15
期刊：
影响因子：
20.3
通讯作者：
Amadori, S
中科院分区：
文献类型：
--
作者：
Del Poeta, G;Venditti, A;Amadori, S
不能进行细胞凋亡是急性髓系白血病（AML）多药耐药的一个重要机制，线粒体凋亡蛋白的分析可能是一个重要的预后工具，以预测结果。采用流式细胞术检测55例初治AML患者的Bcl-2和Bax癌蛋白，并应用抗Bcl-2单克隆抗体（MoAb）和抗Bax MoAb。结果表示为通过将bax平均荧光强度（MFI）除以bcl-2 MFI而获得的指数（bax/bcl-2）。bax/bcl-2比值较低与法美英（FAB）M0-M1分类（P=.00001）和CD 34> 20%（P <.00001）相关。CD 34或CD 117 MFI与bax/bcl-2值之间存在显著的负相关（r = -.40，P < .000 001和r = -.29，P = .000 002），证实未成熟与该指数一致。此外，较低的bax/bcl-2水平与低风险细胞遗传学相关（P = .0002）。bax/bcl-2水平较高的患者完全缓解率明显较高（79%对45%; P = 0.00001）。bax/bcl-2水平高的患者总生存期（OS）和无病生存期（DFS）均较长（P = 0.00001和0.019）。值得注意的是，bax/bcl-2水平可以准确预测细胞遗传学正常或未知患者的临床反应和结局。事实上，在这147例患者中，bax/bcl-2比值越高，CR率越高（86%对42%; P <0.00001），OS越长（P = 0.0016）。多变量分析证实了bax/bcl-2比值的独立预后价值。因此，线粒体癌蛋白，如bcl-2和bax，代表了临床结果的敏感指标和新的促凋亡分子的潜在靶点，以规避化疗耐药性。
The inability to undergo apoptosis is a crucial mechanism of multidrug resistance in acute myeloid leukemia (AML), and the analysis of mitochondrial apoptotic proteins may represent a significant prognostic tool to predict outcome. Bcl-2 and Bax oncoproteins were evaluated in 55 de novo AML patients (pts) by flow cytometry using an anti-bcl-2 monoclonal antibody (MoAb) and an anti-bax MoAb. The results were expressed as an index (bax/bcl-2) obtained by dividing bax mean fluorescence intensity (MFI) and bcl-2 MFI. Lower bax/bcl-2 ratio was associated with French-American-British (FAB) M0-M1 classes (P=.00001) and CD34 more than 20% (P < .000 01). There were striking inverse correlations between CD34 or CD117 MFI and bax/bcl-2 values (r = -.40, P < .000 001 and r = -.29, P = .000 002), confirming that immaturity is consistent with this index. Moreover, lower bax/bcl-2 levels were correlated with poor-risk cytogenetics (P = .0002). A significant higher complete remission (CR) rate was found in pts With higher bax/bcl-2 levels (79% versus 45%; P = .000 01). Also, both a longer overall survival (OS) and disease-free survival (DFS) were observed in pts With higher bax/bcl-2 levels (P = .000 01 and = .019). Noteworthy, bax/bcl-2 levels accurately predicted the clinical response and outcome of pts with normal or unknown cytogenetics. Indeed, within this subset of 147 pts, higher bax/bcl-2 ratio was significantly associated both with a higher CR rate (86% versus 42%; P < .000 01) and a longer OS (P = .0016). The independent prognostic value of bax/bcl-2 ratio was confirmed in multivariate analysis Therefore, mitochondrial oncoproteins, such as bcl-2 and bax, represent both sensitive indicators of clinical outcome and potential targets of novel proapoptotic molecules in order to circumvent chemoresistance.