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 Blood, 1 November 2008, Vol. 112, No. 9, pp. 3818-3826.
Prepublished online as a Blood First Edition Paper on August 5, 2008; DOI 10.1182/blood-2008-02-138933.

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NEOPLASIA

IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma

Katherine R. Calvo1, Bhavana Dabir1, Alexandra Kovach1, Christopher Devor2, Russell Bandle2, Amelia Bond2, Joanna H. Shih3, and Elaine S. Jaffe1

1 Hematopathology Section, Laboratory of Pathology (LP); 2 Clinical Proteomics Core Lab, LP; and 3 Division of Cancer Treatment and Diagnosis Biometric Research Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD

Follicular lymphoma (FL) is characterized by constitutive expression of Bcl-2 as a consequence of t(14;18). Evidence suggests factors in the lymph node microenvironment, related to intratumoral T cells, macrophages, and dendritic cells, play a role in the disease process. We generated proteomic cytokine profiles of FL (N = 50) and follicular hyperplasia (FH; N = 23). A total of 10 cytokines were assayed using ultrasensitive multiplex enzyme-linked immunosorbent assays: IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-13, IL-12p70, tumor necrosis factor-{alpha}, and interferon-{gamma}. Each cytokine showed overall lower protein concentrations in FL, with the exception of IL-4, which was nearly 5 times higher in FL than FH (P = .005). Using reverse-phase protein microarrays (RPMAs), we evaluated the activation state of several intracellular signaling proteins downstream of cytokine receptors. Basal Erk phosphorylation was approximately 4 times greater in FL than FH (P < .001), with similar findings for Mek; Stat-6 showed weak basal phosphorylation that was approximately twice as high in FL than in FH (P = .012). In conclusion, the FL microenvironment contains increased levels of IL-4, with prominent tumor basal phosphorylation of Erk. These findings suggest IL-4, Erk, and possibly Stat-6 may play a role in the biology of FL and may serve as targets for future therapies.


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