mTORC1 activity is essential for erythropoiesis and B cell lineage commitment

Abstract

Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates phosphoinositide-3-kinase (PI3K)/AKT signalling. This pathway is involved in a plethora of cellular functions including protein and lipid synthesis, cell migration, cell proliferation and apoptosis. In this study, we proposed to delineate the role of mTORC1 in haemopoietic lineage commitment using knock out (KO) mouse and cell line models. Mx1-cre and Vav-cre expression systems were used to specifically target Raptorfl/fl (mTORC1), either in all tissues upon poly(I:C) inoculation, or specifically in haemopoietic stem cells, respectively. Assessment of the role of mTORC1 during the early stages of development in Vav-cre+Raptorfl/fl mice, revealed that these mice do not survive post birth due to aberrations in erythropoiesis resulting from an arrest in development at the megakaryocyte-erythrocyte progenitor stage. Furthermore, Raptor-deficient mice exhibited a block in B cell lineage commitment. The essential role of Raptor (mTORC1) in erythrocyte and B lineage commitment was confirmed in adult Mx1-cre+Raptorfl/fl mice upon cre-recombinase induction. These studies were supported by results showing that the expression of key lineage commitment regulators, GATA1, GATA2 and PAX5 were dysregulated in the absence of mTORC1-mediated signals. The regulatory role of mTOR during erythropoiesis was confirmed in vitro by demonstrating a reduction of K562 cell differentiation towards RBCs in the presence of established mTOR inhibitors. While mTORC1 plays a fundamental role in promoting RBC development, we showed that mTORC2 has an opposing role, as Rictor-deficient progenitor cells exhibited an elevation in RBC colony formation ex vivo. Collectively, our data demonstrate a critical role played by mTORC1 in regulating the haemopoietic cell lineage commitment.

mTORC1 activity is essential for disease progression in chronic lymphocytic leukemia

“…1B). These data suggest an early block in B cell development in Mx1-Raptor cKO mice compared to controls, in agreement with previous studies ( 12-14, 16 ). Excision was also validated at the protein level with a significant reduction of RAPTOR expression in the spleen, and thymus in Mx1-Raptor cKO mice (Fig.…”

“…We and others have previously established that Mx1-Raptor cKO mice displayed significant disruption to B cell development and maturation, at least in part due to a block in B cell lineage commitment at the LSK stage ( 11-14 ). Furthermore, a similar early block was noted early in T lineage commitment in the absence of mTORC1 ( 24 ).…”

Effect of Glucocorticosteroids in Diamond-Blackfan Anaemia: Maybe Not as Elusive as It Seems

“…It seems to be induced by ROS [60], hypoxia [87] or some mTOR-independent pathways [88]. However, mTORindependent autophagy may not be sufficient for proper RBC development [89]. Therefore, autophagy induction may offer a possible target for future treatment of DBA patients [86].…”

Sex and Gender Aspects for Patient Stratification in Allergy Prevention and Treatment

“…The downstream target of mTORc2 serine/threonine-protein kinase (SGK1) blocks Th1 cell lineage commitment and and promotes Th2 development. Furthermore deletion of another target of mTORc2 the GTPase RhoA reduces glycolisis and IL-4 secretion and Th1, Th2 and Th17 growth and fuction is highly glycolytic [39,44]. To enhance Tregs generation in normally activated conditions, the simultaneous inhibition of mTORC1 and mTORc2 [41,45] is required.…”