文章：

急性骨髓性白血病中钙蛋白酶活性升高与钙蛋白酶抑制剂表达降低相关

Elevated calpain activity in acute myelogenous leukemia correlates with decreased calpastatin expression

原文发布日期：2012-01-13

DOI: 10.1038/bcj.2011.50

类型: Original Article

开放获取: 是

英文摘要：

Calpains are intracellular cysteine proteases that have crucial roles in many physiological and pathological processes. Elevated calpain activity has been associated with many pathological states. Calpain inhibition can be protective or lethal depending on the context. Previous work has shown that c-myc transformation regulates calpain activity by suppressing calpastatin, the endogenous negative regulator of calpain. Here, we have investigated calpain activity in primary acute myelogenous leukemia (AML) blast cells. Calpain activity was heterogeneous and greatly elevated over a wide range in AML blast cells, with no correlation to FAB classification. Activity was particularly elevated in the CD34+CD38− enriched fraction compared with the CD34+CD38+ fraction. Treatment of the cells with the specific calpain inhibitor, PD150606, induced significant apoptosis in AML blast cells but not in normal equivalent cells. Sensitivity to calpain inhibition correlated with calpain activity and preferentially targeted CD34+CD38− cells. There was no correlation between calpain activity and p-ERK levels, suggesting the ras pathway may not be a major contributor to calpain activity in AML. A significant negative correlation existed between calpain activity and calpastatin, suggesting calpastatin is the major regulator of activity in these cells. Analysis of previously published microarray data from a variety of AML patients demonstrated a significant negative correlation between calpastatin and c-myc expression. Patients who achieved a complete remission had significantly lower calpain activity than those who had no response to treatment. Taken together, these results demonstrate elevated calpain activity in AML, anti-leukemic activity of calpain inhibition and prognostic potential of calpain activity measurement.

摘要翻译： 

钙蛋白酶是一类细胞内半胱氨酸蛋白酶，在多种生理和病理过程中发挥关键作用。其活性升高与多种病理状态相关。钙蛋白酶抑制在不同情境下可产生保护或致死效应。既往研究表明，c-myc转化通过抑制内源性负调控因子钙蛋白酶抑素（calpastatin）来调控钙蛋白酶活性。本研究对原发性急性髓系白血病（AML）原始细胞中的钙蛋白酶活性进行了探究。结果显示，AML原始细胞中钙蛋白酶活性呈异质性且显著升高，范围广泛，与FAB分型无相关性。CD34+CD38−富集亚群的活性尤为高于CD34+CD38+亚群。采用特异性钙蛋白酶抑制剂PD150606处理可诱导AML原始细胞显著凋亡，但对正常对应细胞无影响。对钙蛋白酶抑制的敏感性与钙蛋白酶活性相关，且优先靶向CD34+CD38−细胞。钙蛋白酶活性与p-ERK水平无相关性，提示ras通路可能并非AML中钙蛋白酶活性的主要贡献因素。钙蛋白酶活性与钙蛋白酶抑素呈显著负相关，表明后者是这些细胞中活性的主要调控因子。对既往发表的多种AML患者微阵列数据分析显示，钙蛋白酶抑素与c-myc表达呈显著负相关。达到完全缓解的患者其钙蛋白酶活性显著低于治疗无反应者。综上所述，这些结果证实了AML中钙蛋白酶活性升高、钙蛋白酶抑制的抗白血病活性，以及钙蛋白酶活性检测的预后潜力。

原文链接：

Elevated calpain activity in acute myelogenous leukemia correlates with decreased calpastatin expression