MTORC1 and mTORC2 control normal and neoplastic mast cell homoeostasis through regulation of cell division rather than maintenance of survival (151.20)

Abstract

Abstract Mature mast cells are terminally differentiated and non-dividing. However, a pathologic increase in mast cells is associated with the myeloproliferative disorder mastocytosis which has been linked to expression of an activating mutation (D816V) in the mast cell growth factor receptor, KIT. We found that in primary human mast cells developed from peripheral blood CD34+ progenitor cells, KIT activation led to activation of mTORC1 and mTORC2 pathways through phosphorylation of mTOR (mammalian target of rapamycin) at S2481 and that these pathways were constitutively activated in both D816V positive (HMC-1.2) and negative (HMC-1.1, LAD2) neoplastic human mast cells. A dual acting inhibitor of the mTORC1 and mTORC2 pathways, Torin1, and a more selective mTORC1 inhibitor, Rapamycin, abolished proliferation of the malignant mast cells regardless of the presence of the D816V mutation. However, little reduction in numbers of the non-dividing primary mast cells was observed. The effects of the inhibitors on cell proliferation correlated to downregulation of mTORC1 and mTORC2 pathways which was verified by shRNA. Furthermore, no evidence of apoptosis in response to the inhibitors was observed in either neoplastic or primary mast cells. Collectively, our data demonstrate that by targeting the mTORC1 and mTORC2 pathways, it may be possible to inhibit the proliferation of rapidly dividing mast cell populations associated with mastocytosis while leaving normal mast cells largely unaffected.