This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gulmann, C. Articles by Feldman, A. L. Search for Related Content PubMed PubMed Citation Articles by Gulmann, C. Articles by Feldman, A. L.

Proteomic Analysis of Apoptotic Pathways Reveals Prognostic Factors in Follicular Lymphoma

Authors' Affiliations: ¹ National Cancer Institute-Food and Drug Administration Clinical Proteomics Program, Laboratory of Pathology, and ² Genetics Branch, National Cancer Institute; ³ Tissue Proteomics Unit, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland; ⁴ National Institute on Aging, Baltimore, Maryland; and ⁵ Department of Pathology, Children's National Medical Center, Washington, District of Columbia

Requests for reprints: Andrew L. Feldman, Laboratory of Pathology, National Cancer Institute, Room 2A33, Building 10, 10 Center Drive Bethesda, MD 20892. Phone: 301-594-2945; Fax: 301-402-2415; E-mail: feldmana{at}mail.nih.gov.

Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma and generally is incurable. Reliable prognostic markers to differentiate patients who progress rapidly from those who survive for years with indolent disease have not been established. Most cases overexpress Bcl-2, but the pathogenesis of FL remains incompletely understood. To determine whether a proteomic approach could help overcome these obstacles, we procured lymphoid follicles from 20 cases of FL and 15 cases of benign follicular hyperplasia (FH) using laser capture microdissection. Lysates were spotted on reverse-phase protein microarrays and probed with 21 antibodies to proteins in the intrinsic apoptotic pathway, including those specific for posttranslational modifications such as phosphorylation. A panel of three antibodies [phospho-Akt(Ser473), Bcl-2, and cleaved poly(ADP-ribose) polymerase] segregated most cases of FL from FH. Phospho-Akt(Ser473) and Bcl-2 were significantly increased in FL (P = 0.001 and P < 0.0001, respectively). Additionally, the Bcl-2/Bak ratio completely segregated FL from FH. High ratios of Bcl-2/Bak and Bcl-2/Bax were associated with early death from disease with differences in median survival times of 7.3 years (P = 0.0085) and 3.8 years (P = 0.018), respectively. Using protein microarrays, we identified candidate proteins that may signify clinically relevant molecular events in FL. This approach showed significant changes at the posttranslational level, including Akt phosphorylation, and suggested new prognostic markers, including the Bcl-2/Bak and Bcl-2/Bax ratios. Proteomic end points should be incorporated in larger, multicenter trials to validate the clinical utility of these protein microarray findings.

This article has been cited by other articles:

				E. S. Neeley, S. M. Kornblau, K. R. Coombes, and K. A. Baggerly Variable slope normalization of reverse phase protein arrays Bioinformatics, June 1, 2009; 25(11): 1384 - 1389. [Abstract] [Full Text] [PDF]

				K. R. Calvo, B. Dabir, A. Kovach, C. Devor, R. Bandle, A. Bond, J. H. Shih, and E. S. Jaffe IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma Blood, November 1, 2008; 112(9): 3818 - 3826. [Abstract] [Full Text] [PDF]

				V. Espina, K. H. Edmiston, M. Heiby, M. Pierobon, M. Sciro, B. Merritt, S. Banks, J. Deng, A. J. VanMeter, D. H. Geho, et al. A Portrait of Tissue Phosphoprotein Stability in the Clinical Tissue Procurement Process Mol. Cell. Proteomics, October 1, 2008; 7(10): 1998 - 2018. [Abstract] [Full Text] [PDF]

				A. J. VanMeter, A. S. Rodriguez, E. D. Bowman, J. Jen, C. C. Harris, J. Deng, V. S. Calvert, A. Silvestri, C. Fredolini, V. Chandhoke, et al. Laser Capture Microdissection and Protein Microarray Analysis of Human Non-small Cell Lung Cancer: Differential Epidermal Growth Factor Receptor (EGPR) Phosphorylation Events Associated with Mutated EGFR Compared with Wild Type Mol. Cell. Proteomics, October 1, 2008; 7(10): 1902 - 1924. [Abstract] [Full Text] [PDF]

				S. H. Olejniczak, F. J. Hernandez-Ilizaliturri, J. L. Clements, and M. S. Czuczman Acquired Resistance to Rituximab Is Associated with Chemotherapy Resistance Resulting from Decreased Bax and Bak Expression Clin. Cancer Res., March 1, 2008; 14(5): 1550 - 1560. [Abstract] [Full Text] [PDF]

				F. Rojo, L. Najera, J. Lirola, J. Jimenez, M. Guzman, M. D. Sabadell, J. Baselga, and S. R. y Cajal 4E-Binding Protein 1, A Cell Signaling Hallmark in Breast Cancer that Correlates with Pathologic Grade and Prognosis Clin. Cancer Res., January 1, 2007; 13(1): 81 - 89. [Abstract] [Full Text] [PDF]

				L. Leseux, S. M. Hamdi, T. al Saati, F. Capilla, C. Recher, G. Laurent, and C. Bezombes Syk-dependent mTOR activation in follicular lymphoma cells Blood, December 15, 2006; 108(13): 4156 - 4162. [Abstract] [Full Text] [PDF]

				S. H. Olejniczak, J. L. Clements, N. Bangia, F. J. Hernandez-Ilizaliturri, and M. S. Czuczman Down-Regulation of Bax and Bak in Immuno-Chemotherapy Resistant Non-Hodgkin's Lymphoma Cells. Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 4758 - 4758. [Abstract] [PDF]

				K. E. Krueger and S. Srivastava Posttranslational Protein Modifications: Current Implications for Cancer Detection, Prevention, and Therapeutics Mol. Cell. Proteomics, October 1, 2006; 5(10): 1799 - 1810. [Full Text] [PDF]