Ghosh Joydeep, Kapur Reuben
Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Exp Hematol. 2017 Jun;50:13-21. doi: 10.1016/j.exphem.2017.02.004. Epub 2017 Mar 22.
Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-p70 ribosomal protein kinase 1 (S6K1) signaling pathway occurs frequently in acute myeloid leukemia (AML) patients. This pathway also plays a critical role in maintaining normal cellular processes. Given the importance of leukemia stem cells (LSCs) in the development of minimal residual disease, it is critical to use therapeutic interventions that target the LSC population to prevent disease relapse. The mTORC1-S6K1 pathway has been identified as an important regulator of hematopoietic stem cell (HSC) and LSC functions. Both HSC and LSC functions require regulation of key cellular processes including proliferation, metabolism, and autophagy, which are regulated by mTORC1 pathway. Despite the mTORC1-S6K1 pathway being a critical regulator of AML initiation and progression, inhibitors of this pathway alone have yielded mixed results in clinical studies. Recent studies have identified strategies to develop new mTORC1-S6K1 inhibitors such as RapaLink-1, which could circumvent the drug resistance observed in AML cells and in LSCs. Here, we review recent advances made in identifying the role of different components of this pathway in the regulation of HSCs and LSCs and discuss possible therapeutic approaches.
雷帕霉素复合物1（mTORC1）-p70核糖体蛋白激酶1（S6K1）信号通路失调在急性髓系白血病（AML）患者中频繁发生。该通路在维持正常细胞过程中也起着关键作用。鉴于白血病干细胞（LSCs）在微小残留病发生发展中的重要性，使用针对LSC群体的治疗干预措施以预防疾病复发至关重要。mTORC1-S6K1通路已被确定为造血干细胞（HSC）和LSC功能的重要调节因子。HSC和LSC的功能都需要对包括增殖、代谢和自噬在内的关键细胞过程进行调节，而这些过程由mTORC1通路调控。尽管mTORC1-S6K1通路是AML起始和进展的关键调节因子，但仅该通路的抑制剂在临床研究中取得的结果喜忧参半。最近的研究已经确定了开发新型mTORC1-S6K1抑制剂的策略，如RapaLink-1，它可以规避在AML细胞和LSCs中观察到的耐药性。在此，我们综述了在确定该通路不同组分在HSCs和LSCs调节中的作用方面取得的最新进展，并讨论了可能的治疗方法。
