PARP抑制剂诱导急性髓系白血病干细胞凋亡的机制研究

The PI3K/AKT and mTOR signaling pathways are aberrant activated in most of acute myeloid leukemia (AML). The phosphorylated AKT or activitated mTOR pathway signals are detected mostly in the immature blast cell population with the CD34+ CD38-/low phenotype, which are defined as leukemic stem cell (LSC). Our previous studies have shown that PARP inhibitors can induce cell apoptosis via attenuation of AKT and mTOR pathway signaling, demonstrating a new anti-tumor mechanism of PARP inhibitors. Furthermore, leukemic cells showed high sensitivity to these drugs. Accordingly, we hereby present the following presumption that PARP inhibitors may kill the LSC population through suppressing AKT and mTOR pathway, the combination of PARP inhibitors and chemotherapy may show a synergistic action on curing acute leukemia. To test the hypothesis, we intend to apply research on multiple levels, including AML cell lines, primary AML cells and AML NOD-SCID mouse models, to investigate the effects of PARP inhibitors on LSC and the mechanisms of suppression of proliferation and induction apoptosis of AML cells. Finally, we hope it can provide new idea to develop a new, ultimately, improved therapy for AML patients.

绝大部分急性髓系白血病（AML）存在AKT和mTOR通路的异常活化，且携带有异常活化的AKT/mTOR的细胞群主要为CD34+、CD38Low/Neg的原始细胞,即LSC细胞。申请人前期实验发现PARP抑制剂抗肿瘤作用的新机制，即通过降低AKT和mTOR通路的活性诱导细胞凋亡，且AML细胞对该药敏感。为此我们提出以下设想，PARP抑制剂可能通过抑制AKT和mTOR通路的活性抑制或杀伤白血病干细胞（LSC）群，与化疗药物联用具有协同的抗白血病作用。为验证这一假说，我们拟通过对AML细胞株、原代细胞及NOD-SCID小鼠异种移植模型的体内外实验研究，从分子、细胞、组织以及动物整体水平等多方面探讨,探索PARP抑制剂对AML细胞及LSC生长增殖和凋亡的作用及其深入机制，以深入阐述PARP抑制剂对AML的治疗作用及其作用机理,为寻求更有效的AML治疗方案提供新的方法和思路。

PI3K/Akt/mTOR通路是细胞存活和代谢的重要信号转导通路，多项研究已经证实多数急性白血病（acute leukemia，AL）患者样本中可检测到PI3K/Akt通路的异常高度激活。Akt/mTOR的激活与白血病的发生、化疗效果和预后密切相关。因此靶向抑制PI3K/Akt/mTOR通路成为治疗白血病的研究热点。本项目书通过对AL细胞株、原代细胞及NOD-SCID小鼠异种移植模型的体内外实验研究，从分子、细胞、组织以及动物整体水平等多方面探讨，阐明PI3K/Akt/mTOR通路抑制对AL的治疗作用及其作用机理。我们的研究发现，通过抑制剂降低该通路的活性，AL细胞系Jurkat、MOLT4、K562、Kasumi-1及原代AL细胞的增殖、存活受到显著抑制。在NOD-SCID小鼠异种移植模型中，PI3K/mTOR抑制剂可显著抑制肿瘤的生长，诱导凋亡，延长小鼠生存期。这些结果为PI3K/Akt/mTOR抑制剂有望用于白血病治疗并协助化疗药物改善疗效提供可能。