Immunogenic apoptosis in human acute myeloid leukemia (AML): primary human AML cells expose calreticulin and release heat shock protein (HSP) 70 and HSP90 during apoptosis
Immunogenic apoptosis in human acute myeloid leukemia (AML): primary human AML cells expose calreticulin and release heat shock protein (HSP) 70 and HSP90 during apoptosis
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DOI：
10.3892/or.2011.1229
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发表时间：
2011-06-01
期刊：
影响因子：
4.2
通讯作者：
Bruserud, Oystein
中科院分区：
文献类型：
--
作者：
Fredly, Hanne;Ersvaer, Elisabeth;Bruserud, Oystein
已有研究表明，常规细胞毒药物和靶向治疗药物均可诱导原代人急性髓系白血病(AML)细胞发生凋亡。然而，垂死的AML细胞的凋亡表型还没有得到广泛的描述。尽管特定的抗白血病免疫反应在急性髓系白血病中很重要，尤其是对于同种异体移植的患者，但死亡的原代人类急性髓系白血病细胞是否表现出与免疫原性凋亡一致的表型特征[钙网蛋白暴露，热休克蛋白(HSP)释放]尚未得到研究。因此，我们研究了体外培养的原代人急性髓系白血病(AML)细胞在单独培养和在抗白血病药物存在的情况下，在自发性(应激诱导)凋亡过程中是否显示钙网蛋白暴露和HSP70/HSP90释放。钙网蛋白的表面暴露以及热休克蛋白70和热休克蛋白90的释放都被检测到，但在不同患者之间表现出很大的差异。当AML细胞在细胞毒性药物(阿糖胞苷、柔红霉素、丝裂霉素)、全反式维甲酸(ATRA)和丙戊酸存在的情况下培养时，这种差异也保持不变。最后，在体内全反式维甲酸治疗期间收集的AML细胞显示，在自发的体外凋亡过程中，钙网蛋白暴露增加，这表明体内药物治疗可以调节细胞凋亡的表型。综上所述，凋亡的AML细胞可以表现出与免疫原性凋亡一致的表型特征，但患者之间存在很大的差异，钙网蛋白暴露/HSP释放的水平似乎取决于患者的个体特征，而不是凋亡诱导剂。
Several previous studies have demonstrated that both conventional cytotoxic drugs as well as targeted therapeutics can induce apoptosis in primary human acute myelogenous leukemia (AML) cells. However, the apoptotic phenotype of dying AML cells has been less extensively characterized. Even though specific antileukemic immune reactivity is important in AML, especially for allotransplanted patients, it has not been investigated whether dying primary human AML cells show phenotypic characteristics consistent with immunogenic apoptosis [calreticulin exposure, heat shock protein (HSP) release]. We therefore investigated whether in vitro cultured primary human acute myeloid leukemia (AML) cells show calreticulin exposure and HSP70/HSP90 release during spontaneous (stress-induced) apoptosis when cultured in medium alone and when cultured in the presence of antileukemic drugs. Both surface exposure of calreticulin and release of HSP70 and HSP90 was detected but showed a wide variation between patients. This variation was also maintained when the AML cells were cultured in the presence of cytotoxic drugs (cytarabine, daunorubicin, mitomycin), all-trans retinoic acid (ATRA) and valproic acid. Finally, AML cells collected during in vivo ATRA therapy showed increased calreticulin exposure during spontaneous in vitro apoptosis, suggesting that in vivo pharmacotherapy can modulate the apoptotic phenotype. To conclude, apoptotic AML cells can show phenotypic characteristics consistent with immunogenic apoptosis, but there is a wide variation between patients and the level of calreticulin exposure/HSP release seems to depend on individual patient characteristics rather than the apoptosis-inducing agent.