Blood Journal
Leading the way in experimental and clinical research in hematology

PKC ζ–mTOR pathway: a new target for rituximab therapy in follicular lymphoma

  1. Ludivine Leseux1,
  2. Guy Laurent1,2,
  3. Camille Laurent3,
  4. Maxime Rigo1,
  5. Amandine Blanc1,
  6. Daniel Olive4, and
  7. Christine Bezombes1
  1. 1INSERM, Unite 563, Centre de Physiopathologie de Toulouse Purpan, Université Toulouse III Paul-Sabatier, Toulouse;
  2. 2Service d'hématologie, Centre Hospitalier Universitaire (CHU) Purpan, Toulouse;
  3. 3Service d'anatomie et cytologie pathologiques, CHU Purpan, Toulouse; and
  4. 4Immunologie des Tumeurs, Institut Paoli-Calmettes, Faculté de Médecine de Marseille, Université de la Méditerranée, Marseille, France


Previous studies have documented that, in malignant B cells, rituximab elicits a complex and not yet totally understood signaling network contributing to its antitumor effect. In this context, we investigated the role of protein kinase C ζ (PKCζ), an atypical PKC isoform, in the cellular response to rituximab. We found that follicular lymphoma cells displayed an increase in PKCζ expression and activity levels, compared with nonmalignant B cells, and that this enzyme was a critical regulator of the classical MAPK module by stimulating Raf-1 kinase activity. PKCζ appeared to be a significant contributor of abnormal mTOR regulation in follicular lymphoma cells through a MAPK-dependent mechanism. Rituximab was found to inhibit the PKCζ/MAPK/mTOR module in these cells but not in other B-cell lymphomas. Importantly, the expression of a constitutively active form of PKCζ resulted in an efficient protection of these cells toward rituximab. Altogether, our study describes a new regulatory component of mTOR pathway in follicular cell lymphoma and demonstrates that PKCζ is a target for rituximab. Therefore, PKCζ could represent an important parameter for rituximab efficacy and a promising target for future targeted therapy in follicular lymphoma.

  • Submitted April 13, 2007.
  • Accepted August 10, 2007.
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