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

Michal Marzec, Xiaobin Liu, Monika Kasprzycka, Agnieszka Witkiewicz, Puthiyaveettil N. Raghunath, Mouna El-Salem, Erle Robertson, Niels Odum, Mariusz A. Wasik

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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.

Original languageEnglish (US)
Pages (from-to)2181-2189
Number of pages9
JournalBlood
Volume111
Issue number4
DOIs
StatePublished - Feb 15 2008

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Interleukin-15
T-cells
Sirolimus
Cutaneous T-Cell Lymphoma
Interleukin-2
Chemical activation
T-Lymphocytes
Mitogen-Activated Protein Kinase Kinases
Phosphatidylinositol 3-Kinases
MAP Kinase Signaling System
Cells
Janus Kinase 1
mechanistic target of rapamycin complex 1
Cell Line
T-Cell Lymphoma
Cell proliferation
Mitogens
Nutrients
Lymphoma
Cell Proliferation

ASJC Scopus subject areas

  • Hematology

Cite this

Marzec, M., Liu, X., Kasprzycka, M., Witkiewicz, A., Raghunath, P. N., El-Salem, M., ... Wasik, M. A. (2008). IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes. Blood, 111(4), 2181-2189. https://doi.org/10.1182/blood-2007-06-095182

IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes. / Marzec, Michal; Liu, Xiaobin; Kasprzycka, Monika; Witkiewicz, Agnieszka; Raghunath, Puthiyaveettil N.; El-Salem, Mouna; Robertson, Erle; Odum, Niels; Wasik, Mariusz A.

In: Blood, Vol. 111, No. 4, 15.02.2008, p. 2181-2189.

Research output: Contribution to journalArticle

Marzec, M, Liu, X, Kasprzycka, M, Witkiewicz, A, Raghunath, PN, El-Salem, M, Robertson, E, Odum, N & Wasik, MA 2008, 'IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes', Blood, vol. 111, no. 4, pp. 2181-2189. https://doi.org/10.1182/blood-2007-06-095182
Marzec, Michal ; Liu, Xiaobin ; Kasprzycka, Monika ; Witkiewicz, Agnieszka ; Raghunath, Puthiyaveettil N. ; El-Salem, Mouna ; Robertson, Erle ; Odum, Niels ; Wasik, Mariusz A. / IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes. In: Blood. 2008 ; Vol. 111, No. 4. pp. 2181-2189.
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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.",
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AU - Witkiewicz, Agnieszka

AU - Raghunath, Puthiyaveettil N.

AU - El-Salem, Mouna

AU - Robertson, Erle

AU - Odum, Niels

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