Role of mTORC1-S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia

摘要

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 (LSC) in the development of minimal residual disease (MRD), it is critical to use therapeutic interventions that target LSC population to prevent disease relapse. 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 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 like RapaLink-1, which could circumvent the drug resistance observed in AML cells as well as in LSC. In this article, we review recent advances made in identifying the role of different components of this pathway in the regulation of HSC and LSC along with possible therapeutic approaches.