# Regulatory role of mTORC1 signaling in osteoblasts in acute myeloid leukemia progression and steady-state hematopoiesis

## TL;DR

This study shows that mTORC1 signaling in bone-forming cells promotes the growth of acute myeloid leukemia and disrupts normal blood cell production.

## Contribution

The study identifies mTORC1 in osteoblasts as a novel regulator of AML progression and hematopoiesis.

## Key findings

- mTORC1 signaling is activated in osteoblasts of AML murine models and clinical specimens.
- Osteoblast-specific mTORC1 activation promotes AML growth, while its inactivation suppresses it.
- The mTORC1-IL-6 axis in osteoblasts contributes to AML progression.

## Abstract

Acute myeloid leukemia (AML) is widely recognized for its intrinsic leukemic-cell-driven regulation as well as its extrinsic niche-driven regulation. Despite mounting evidence that bone-forming osteoblasts provide an endosteal niche for AML cells, the precise mechanism remains to be elucidated. The cell-autonomous mammalian target of rapamycin complex 1 (mTORC1) is involved in the onset and progression of AML. Here, we found that mTORC1 signaling was activated in the osteoblasts of an AML murine model and clinical AML specimens. Osteoblast-specific mTORC1 activation in mice promotes AML growth, whereas mTORC1 inactivation suppresses it. Interleukin-6 (IL-6) was identified through screening as a downstream factor in mTORC1-regulated AML progression. Genetic ablation of the IL-6 receptor in AML cells significantly attenuated AML growth in osteoblast-specific mTORC1-activated mice. Collectively, our results suggest that the mTORC1/IL-6 axis in osteoblastic niche non-autonomously contributes to the AML progression, suggesting a viable therapeutic target for AML.

•mTORC1 signaling is activated in osteoblasts of murine model and clinical specimen of AML•mTORC1 activation in osteoblasts worsens AML progression, and vice versa•mTORC1 activation in osteoblasts disrupts normal hematopoiesis•mTORC1-IL-6 axis in osteoblasts contributes to AML progression

mTORC1 signaling is activated in osteoblasts of murine model and clinical specimen of AML

mTORC1 activation in osteoblasts worsens AML progression, and vice versa

mTORC1 activation in osteoblasts disrupts normal hematopoiesis

mTORC1-IL-6 axis in osteoblasts contributes to AML progression

Cell biology; Cancer