mTORC1 Inactivation Prevents and Eradicates Acute Lymphoblastic T-Cell Leukemia
Authors: Hoshii Takayuki , Kasada Atsuo , Hatakeyama Tomoki , Ohtani Masashi , Tadokoro Yuko , Naka Kazuhito , Ikenoue Tsuneo , Ikawa Tomokatsu , Kawamoto Hiroshi , Araki Kimi , Yamamura Ken-ichi , Iwama Atsushi , Matsuda Satoshi , Hirao Atsushi 
Published: October 2019

mTOR is a serine/threonine kinase that has a central role in the regulation of cell growth and cell metabolism and forms two functionally different complexes, named mTORC1 and mTORC2. Despite the effectiveness of rapamycin, an allosteric mTOR inhibitor, in immunosuppression, the precise roles of mTORCs in T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the earliest development of T-cell progenitors. To understand the physiological role of mTORC1 in T-cell development, we evaluated the effects of mTORC1 inhibition by rapamycin treatment or the genetic deletion of the Raptor gene, an essential component of mTORC1. Raptor deficiency dramatically inhibited the development of CD4/CD8 double-positive (DP) cells. Rapamycin treatment produced similar defects, but to a lesser extent. Deficiency of Raptor, but not Rictor, a mTORC2 component, resulted in abnormality of cell cycle of early T-cell progenitors, associated with instability of the Cyclin D3/CDK6 complex, indicating that mTORC1 and 2 control T-cell development in different manners. When we treated T-cells with a proteasome inhibitor, MG-132, in vitro, the reduction of Cyclin D3 and CDK6 by mTORC1 inactivation was reversed. These data suggest that mTORC1 activity may control the Cyclin D3/CDK6 complex via post-transcriptional mechanisms. In a model of myeloproliferative neoplasm (MPN) and T-cell leukemia (T-ALL) evoked by Kras activation, rapamycin treatment prevents development of T-ALL, but not MPN. After the onset of T-ALL, rapamycin-insensitive Notch-driven T-ALL cells survived in vivo. Raptor deficiency dramatically inhibited proliferation of oncogenic Kras–expressing T-cell progenitors and prevents the development of T-ALL, but not MPN. In contrast to T-cell progenitors, cell cycle of myeloid progenitors was not affected by mTORC1 inactivation. Phosphorylation of p70S6K and 4E-BP1, direct substrates of mTORC1, was apparently decreased in Raptor-deficient myeloid cells. Interestingly, consistent with hypo-phosphorylation of p70S6K and 4E-BP1, rates of newly synthesized protein were significantly reduced in cycling Raptor-deficient progenitors. These data indicate that the impact of mTORC1 deficiency on cell cycle status varies substantially depending on the cell context. In addition, we evaluated the effect of hyperactivation of mTORC1 by Tsc1 deletion on the behavior of T-ALL. Tsc1 deficiency shortened survival, and promoted the cell proliferation, as well as the dissemination of active Notch-driven T-ALL cells in non-hematopoietic tissues. However, strikingly, Raptor deficiency resulted in efficient leukemia eradication. Thus, understanding the cell-context-dependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.

Disclosures:

No relevant conflicts of interest to declare.