Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells
Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells
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DOI：
10.1172/jci35660
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发表时间：
2009-05-01
影响因子：
15.9
通讯作者：
Calabretta, Bruno
中科院分区：
文献类型：
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作者：
Bellodi, Cristian;Lidonnici, Maria Rosa;Calabretta, Bruno
甲磺酸伊马替尼（IM）是一种强效的BCR/ABL酪氨酸激酶抑制剂，已成为慢性髓性白血病（CML）患者的标准一线治疗药物，但在疾病进展阶段耐药频率增加。消除BCR/ABL依赖的细胞内信号会触发细胞凋亡，但尚不清楚这是否会激活其他细胞存活和/或死亡途径。我们在此表明，IM诱导慢性髓性白血病急变期细胞系、慢性髓性白血病原代细胞以及表达p210(BCR/ABL)的髓系前体细胞发生自噬。IM诱导的自噬不涉及c - Abl或Bcl - 2活性，但与内质网应激相关，并且可通过减少细胞内Ca2+而被抑制，这表明它在机制上与IM诱导的细胞凋亡不重叠。我们进一步证明，使用药物抑制剂或对关键自噬基因进行RNA干扰来抑制自噬，可增强IM在细胞系和慢性髓性白血病原代细胞中诱导的细胞死亡。关键的是，酪氨酸激酶抑制剂（TKI），即IM、尼洛替尼或达沙替尼，与自噬抑制剂联合使用，可导致表型和功能上确定的慢性髓性白血病干细胞几乎完全消除。总之，这些发现表明自噬抑制剂可能增强酪氨酸激酶抑制剂在慢性髓性白血病治疗中的疗效。
Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210(BCR/ABL)-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.