mTORC1 is required for normal HSC function, whereas mTORC2 is expendable.
Major finding: mTORC1 is required for normal HSC function, whereas mTORC2 is expendable.
Clinical relevance: mTORC1 and mTORC2 have nonredundant roles in T-ALL development in Pten-null mice.
Impact: Blockade of mTORC2 activity may target leukemic signaling without affecting normal hematopoiesis.
Human leukemias are driven by dysregulation of the signaling pathways that mediate hematopoietic stem cell (HSC) differentiation and self-renewal. In T-cell acute lymphoblastic leukemia (T-ALL) and other types of leukemia, PTEN loss-of-function mutations lead to hyperactive PI3K and mTOR pathway signaling. mTOR inhibitors can block leukemogenesis in Pten-null mouse models, but the underlying mechanism is unclear, given that mTOR exists in 2 independent, multisubunit complexes with different cellular targets. Characterizing the role of each mTOR complex (mTORC) in normal hematopoiesis and leukemogenesis therefore has the potential to improve therapeutic indices and guide the development of mTORC-targeted agents with higher antileukemic activity. Kalaitzidis and colleagues conditionally deleted an mTORC1-specific subunit gene, regulatory associated protein of mTOR (Raptor), in HSCs and observed broad differentiation defects in multiple hematopoietic lineages. Raptor loss also led to cell-cycle and metabolic defects in HSCs and was required for HSC regeneration. In contrast, Magee and colleagues conditionally deleted rapamycin-insensitive companion of mTOR (Rictor), an mTORC2-specific subunit gene, and observed no defects in neonatal or adult hematopoiesis or HSC function. However, despite the differences in their roles in normal blood development, both mTORC1 and mTORC2 were required for leukemogenesis in the absence of PTEN. Kalaitzidis and colleagues observed that deletion of Raptor in a Pten-null HSC background significantly prolonged survival, although the majority of the animals ultimately died. Interestingly, Magee and colleagues found that Rictor deletion similarly prolonged survival but prevented the onset of T-ALL in the majority of Pten-null mice, suggesting that mTORC1 and mTORC2 also have nonoverlapping roles in leukemogenesis. Together, these findings indicate that targeting of mTORC1 may cause adverse effects due to its essential role in normal hematopoiesis and provide a rationale for specific targeting of mTORC2 in T-ALL.
Kalaitzidis D, Sykes SM, Wang Z, Punt N, Tang Y, Ragu C, et al. mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis. Cell Stem Cell 2012;11:429–39.