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IL-2– and IL-15–induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+T lymphocytes

Authors :
Marzec, Michal
Liu, Xiaobin
Kasprzycka, Monika
Witkiewicz, Agnieszka
Raghunath, Puthiyaveettil N.
El-Salem, Mouna
Robertson, Erle
Odum, Niels
Wasik, Mariusz A.
Source :
Blood; February 2008, Vol. 111 Issue: 4 p2181-2189, 9p
Publication Year :
2008

Abstract

We examined functional status, activation mechanisms, and biologic role of the mTORC1 signaling pathway in malignant CD4+T cells derived from the cutaneous T-cell lymphoma (CTCL). Whereas the spontaneously growing CTCL-derived cell lines displayed persistent activation of the TORC1 as well as the PI3K/Akt and MEK/ERK pathways, the IL-2–dependent cell lines activated the pathways in response to IL-2 and IL-15 but not IL-21. Activation of mTORC1 and MEK/ERK was nutrient dependent. The mTORC1, PI3K/Akt, and MEK/ERK pathways could also be activated by IL-2 in the primary leukemic, mitogen-preactivated CTCL cells. mTORC1 activation was also detected in the CTCL tissues in the lymphoma stage–dependent manner with the highest percentage of positive cells present in the cases with a large cell transformation. Rapamycin inhibited mTORC1 signaling and suppressed CTCL cell proliferation but showed little effect on their apoptotic rate when used as a single agent. Activation of the mTORC1, PI3K/Akt, and MEK/ERK pathways was strictly dependent on the Jak3 and Jak1 kinases. Finally, mTORC1 activation was transduced preferentially through the PI3K/Akt pathway. These findings document the selective γc-signaling cytokine-mediated activation of the mTORC1 pathway in the CTCL cells and suggest that the pathway represents a therapeutic target in CTCL and, possibly, other T-cell lymphomas.

Details

Language :
English
ISSN :
00064971 and 15280020
Volume :
111
Issue :
4
Database :
Supplemental Index
Journal :
Blood
Publication Type :
Periodical
Accession number :
ejs56990515
Full Text :
https://doi.org/10.1182/blood-2007-06-095182