Submitted May 30, 2006
Accepted July 28, 2006
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*
Inserm U563-PTP Departement d'Oncogenese et Signalisation dans les Cellules Hematopoietiques, France
INSERM U563 - CPTP, Departement Lipoproteines et Mediateurs Lipidiques, CHU Purpan, France
Plateau technique d'histopathologie experimentale, IFR 30, CHU Purpan, Toulouse cedex 3, France
Service d'hematologie, Centre Hospitalier Universitaire Purpan, Place Dr Baylac, France
* Corresponding author; email: christine.bezombes-cagnac{at}toulouse.inserm.fr.
The mammalian Target of Rapamycin (mTOR) is emerging as a promising target for anti-tumor therapy. However, the mechanism which contributes to its regulation in B lymphomas remains unknown. This study shows that in follicular lymphoma (FL) cells, mTOR is active as they displayed rapamycin-sensitive phosphorylation of p70S6 kinase and 4E-BP1. Moreover, immunohistochemistry applied on lymph node tissue sections obtained from FL patients revealed that, in most cases, p70S6 kinase was highly phosphorylated, compared to normal tonsil. In FL cells, mTOR was found to be under control of both phospholipase D (PLD) and phosphatidylinositol 3-kinase (PI3K). Moreover, we demonstrated that Syk plays a central role in mTOR activation as we found that both expression and activity are elevated compared to normal or chronic lymphocytic leukemia B cells. We also provide evidences 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 plays a critical function in follicular lymphoma survival, and therefore, that Syk could be a promising new target for B-lymphoma therapy.
