Department of Hematology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China.
Eur J Haematol. 2014 Feb;92(2):111-20. doi: 10.1111/ejh.12202. Epub 2014 Jan 6.
BCR-ABL fusion gene typically causes a type of acute lymphoblastic leukemia (ALL), known as Ph+ ALL. Although imatinib (IM) treatment induced high rates of complete response (CR), serious acute and late complications are frequent, whereas more vexatiously resistance to chemotherapy and clinical relapse develops. Therefore, the efficacy of treatment in Ph+ ALL is still to be determined. In this study, we focused our attention on the potential benefit of rapamycin (RAPA), an mammalian target of rapamycin (mTOR) inhibitor, in combination with IM on a Ph+ ALL cell line SUP-B15 and a primary Ph+ ALL sample in vitro. Analysis of cell proliferation showed that RAPA (50 nm) plus IM exerted good synergistic effect on Ph+ ALL cells. Notably, we found that IM treatment induced the abnormal activation of the components of mTOR signaling pathway and p-BCR-ABL, whereas RAPA potently eliminated this deleterious side effect induced by IM and might overcome the resistance to IM. The synergistic effect was also associated with the increase in autophagy, which seemed to have an opposite role with apoptosis in Ph+ ALL cells, and cell cycle arrest in G1 phase. Altogether, our results suggested that IM in combination with RAPA was more effective for Ph+ ALL cells than IM alone.
BCR-ABL 融合基因通常会导致一种称为 Ph+ALL 的急性淋巴细胞白血病（ALL）。虽然伊马替尼（IM）治疗诱导了很高的完全缓解（CR）率，但严重的急性和晚期并发症很常见，而且更令人烦恼的是对化疗和临床复发的耐药性。因此，Ph+ALL 的治疗效果仍有待确定。在这项研究中，我们专注于雷帕霉素（RAPA）的潜在益处，雷帕霉素是一种哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，与 IM 联合用于 Ph+ALL 细胞系 SUP-B15 和体外 Ph+ALL 样本。细胞增殖分析表明，RAPA（50nm）加 IM 对 Ph+ALL 细胞具有良好的协同作用。值得注意的是，我们发现 IM 治疗诱导 mTOR 信号通路和 p-BCR-ABL 的组成部分异常激活，而 RAPA 则有力地消除了 IM 诱导的这种有害副作用，并可能克服对 IM 的耐药性。协同作用还与自噬的增加有关，自噬在 Ph+ALL 细胞中似乎与细胞凋亡具有相反的作用，并导致细胞周期停滞在 G1 期。总的来说，我们的结果表明，与单独使用 IM 相比，IM 联合 RAPA 对 Ph+ALL 细胞更有效。
