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Blood, 15 December 2006, Vol. 108, No. 13, pp. 4156-4162.
Prepublished online as a Blood First Edition Paper on August 15, 2006; DOI 10.1182/blood-2006-05-026203.
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NEOPLASIA
Syk-dependent mTOR activation in follicular lymphoma cells
Ludivine Leseux,
Safouane M. Hamdi,
Talal al Saati,
Florence Capilla,
Christian Recher,
Guy Laurent, and
Christine Bezombes
From the Institut national de la santé et de la recherche médicale (INSERM) U563–Centre de Physiopathologie Toulouse Purpan (CPTP), Département d'Oncogenèse et Signalisation dans les Cellules Hématopoïétiques, Centre Hospitalier Universitaire (CHU) Purpan–BP3028, Toulouse, France; INSERM U563-CPTP, Département Lipoprotéines et Médiateurs Lipidiques, CHU Purpan–BP3028, Toulouse, France; Plateau technique d'histopathologie expérimentale, Institut Fédératif de Recherche (IFR) 30, CHU Purpan–BP3028, Toulouse, France; and Service d'hématologie, Centre Hospitalier Universitaire Purpan, Toulouse, France.
The mammalian target of rapamycin (mTOR) is emerging as a promising target for antitumor therapy. However, the mechanism that contributes to its regulation in B lymphomas remains unknown. This study shows that in follicular lymphoma (FL) cells, mTOR is active because the cells displayed rapamycin-sensitive phosphorylation of p70S6 kinase and 4E-BP1. Moreover, immunohistochemistry applied on lymph node tissue sections obtained from patients with FL revealed that, in most cases, p70S6 kinase was highly phosphorylated compared to normal tonsillar tissue. In FL cells, mTOR was under control of both phospholipase D (PLD) and phosphatidylinositol 3-kinase (PI3K). Moreover, we demonstrated that Syk plays a central role in mTOR activation because we found that both expression and activity are elevated compared to normal or chronic lymphocytic leukemia B cells. We also provide evidence that Syk operates through PLD- and PI3K-independent pathways. Finally, Syk inhibition by piceatannol or by siRNA plasmids resulted in a potent inhibition of mTOR activity in FL cells, as well as in mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma. These findings suggest that the Syk-mTOR pathway has a critical function in FL survival, and therefore, that Syk could be a promising new target for B-lymphoma therapy.
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