mTORC1 in osteoblastic niche regulates progression of acute myeloid leukemia.

Abstract

Hematopoieticstem cells(HSCs) and leukemic stem cells(LSCs) have self-renewal ability to maintain normal hematopoiesis and leukemia propagation, respectively. Recently, it has been reported that bone forming osteoblasts provide a microenvironment for LSCs and are implicated in pathogenesis and progression of leukemia as an osteoblastic niche in bone marrow. The mTOR complex 1 (mTORC1), a member of the serine/threonine kinases, is known to regulate the cellular function in various cell types. Although the role of osteoblastic mTORC1 on bone mass accrual has been investigated, here we show a critical role of mTORC1 in regulating normal hematopoiesis and leukemia progression through its expression in osteoblasts in mice. Using a mouse models of acute myeloid leukemia (AML), we revealed that AML cells enhance the mTORC1 activity in osteoblasts in vivo and in vitro. Subsequent analyses determined that inactivation of Tsc1, a negative regulator of mTORC1, in osteoblasts results in a marked acceleration of AML. These findings highlight a critical role of mTORC1 in normal hematopoiesis and leukemia propagation, at least in part, through its expression in osteoblastic niche.