Abstract
miR-150 functions as a tumor suppressor in malignancies of the lymphocyte lineage and its expression is significantly reduced in these cells. However, the mechanism of miR-150 repression is unknown and so are pharmacological interventions that can reverse it. Here, we report that reduced expression of miR-150 in human Jurkat T-cell acute lymphoblastic leukemia (T-ALL) cells is mediated by constitutive mTOR signaling, a common characteristic of T-ALL cell lines and clinical isolates. Activating mTOR signaling in non-malignant T cells also resulted in a significant miR-150 down-regulation. Conversely, treatment with a pharmacological mTOR inhibitor, rapamycin, increased miR-150 expression in a dose-dependent manner in Jurkat cells, as well as in other leukemia cells. Interestingly, ectopic over-expression of miR-150 acted in a feed-forward loop and further sensitized Jurkat cells to a rapamycin-induced cell cycle arrest by targeting a large network of cell cycle genes. These findings suggest that miR-150 is normally expressed in quiescent T lymphocytes to reinforce an anti-proliferative state, and that mTOR signaling promotes cell proliferation in part by inhibiting miR-150 expression. Restoration of the miR-150-dependent anti-proliferative loop constitutes a novel mechanism underlying the efficacy of rapamycin in a T-ALL cell line. Further investigation of this mechanism in clinical isolates of T-ALL and other hematopoietic malignancies could help better guide development of targeted therapies.
Original language | English (US) |
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Pages (from-to) | 1-9 |
Number of pages | 9 |
Journal | Leukemia Research |
Volume | 74 |
DOIs | |
State | Published - Nov 2018 |
Externally published | Yes |
Keywords
- Acute lymphoblastic leukemia
- Cell cycle
- Gene network
- Jurkat
- Proliferation
- Rapamycin
- mTOR
- miR-150
- microRNA
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research