Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Abstract

mTOR is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants. Recent studies have shown that fine-tuning of the activity of mTOR complexes contributes to organogenesis and tumorigenesis. Although rapamycin, an allosteric mTOR inhibitor, is an effective immunosuppressant, the precise roles of mTOR complexes in early T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the development of both early T-cell progenitors and leukemia. Deletion of Raptor, an essential component of mTORC1, produced defects in the earliest development of T-cell progenitors in vivo and in vitro. Deficiency of Raptor resulted in cell cycle abnormalities in early T-cell progenitors that were associated with instability of the Cyclin D2/D3-CDK6 complexes; deficiency of Rictor, an mTORC2 component, did not have the same effect, indicating that mTORC1 and -2 control T-cell development in different ways. In a model of myeloproliferative neoplasm and T-cell acute lymphoblastic leukemia (T-ALL) evoked by Kras activation, Raptor deficiency dramatically inhibited the cell cycle in oncogenic Kras-expressing T-cell progenitors, but not myeloid progenitors, and specifically prevented the development of T-ALL. Although rapamycin treatment significantly prolonged the survival of recipient mice bearing T-ALL cells, rapamycin-insensitive leukemia cells continued to propagate in vivo. In contrast, Raptor deficiency in the T-ALL model resulted in cell cycle arrest and efficient eradication of leukemia. Thus, understanding the cell-contextdependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.

In vivo, Argonaute-bound microRNAs exist predominantly in a reservoir of low molecular weight complexes not associated with mRNA

“…S16B). In vivo, mTOR is a critical component of signal transduction-induced thymic T-cell maturation (23,24) and development of the embryonic heart (25). Consistent with these observations, we found increased phosphorylation of the mTOR targets S6, S6 kinase, and 4E-BP1 when comparing freshly isolated thymocytes to mature T cells or embryonic heart to adult heart ( Fig.…”

mTORC signaling in hematopoiesis

“…The data indicate that mTOR signaling is important for HSC aging [43]. Rictor-NULL BM contributed to lower levels of the lymphoid lineages [44,45] cKO (Lck-Cre) T cells Deletion of Rictor impaired Notch-driven proliferation and differentiation of pre-T cells [49] Raptor cKO (Mx-Cre) BM Raptor KO BM cells cannot reconstitute the recipients [44] cKO (Lck-Cre) T cells Deletion of Raptor resulted in cell cycle abnormalities in early T cell progenitors [47] cKO (Vav-Cre) RBCs Raptor-deficient mice acquired anemia [57] RHEB cKO (CD4-Cre) T cells Rheb-deficient CD8 + T cells failed to differentiate into effector cells but retained memory characteristics [54] PTEN cKO (Mx-Cre) BM Pten-deficient adult HSCs gave only transient multi-lineage reconstitution that lasted less than 16 weeks after transplantation in all recipient mice [45] Sin1 KO T cells Sin1 deficiency results in an increased proportion of Foxp3(+) natural T-regulatory (nTreg) cells in the thymus [97] Deficiency in Raptor, an essential component of mTORC1, leads to the expansion of CD48 +…”

“…Evidence has shown that mTORC1 plays a more prominent role than mTORC2 in the development of early T cell progenitors. The deletion of Raptor, but not Rictor, resulted in cell cycle abnormalities in early T cell progenitors and generated defective T cell progenitors during the early T cell development in vivo and in vitro [47]. Under steady-state conditions, mTOR activity is kept low to allow normal T cell homeostasis.…”

“…The hyper-activation of mTORC1 has been observed and can be inhibited by γ-secretase inhibitors (GSIs), which would abolish Notch1 signaling transduction, in T-ALLs induced by mutant Notch [68][69][70]. Furthermore, the deletion of Raptor in a NOTCH1-driven T-ALL mouse model prolonged the survival of mice, indicating that mTORC1 is required for lymphomagenesis [47]. In addition, the transformation of Rictor −/− hematopoietic bone marrow precursors by Notch cleaved intracellular polypeptide (ICN1) was also significantly repressed compared with control cells, as evidenced by prolonged survival in the Rictor −/− group.…”

Defining the Domain Arrangement of the Mammalian Target of Rapamycin Complex Component Rictor Protein

“…In contrast, mTORC1 regulators Raptor and Rheb are dispensable for NKT17 differentiation (Wei et al, 2014). In contrast, loss of mTOR complex 1 (deletion of Raptor) induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells, while deficiency of Rictor, an mTORC2 component, did not have the same effect (Hoshii et al, 2014). mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and nonneoplastic human mast cells (Smrz et al, 2011).…”