Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma

Christian Gulmann, Virginia Espina, Emanuel Petricoin, Dan L. Longo, Mariarita Santi, Turid Knutsen, Mark Raffeld, Elaine S. Jaffe, Lance A. Liotta, Andrew L Feldman

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)5847-5855
Number of pages9
JournalClinical Cancer Research
Volume11
Issue number16
DOIs
StatePublished - Aug 15 2005
Externally publishedYes

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Follicular Lymphoma
Proteomics
Protein Array Analysis
Hyperplasia
Phosphorylation
Laser Capture Microdissection
Poly(ADP-ribose) Polymerases
Antibodies
Post Translational Protein Processing
Non-Hodgkin's Lymphoma
Multicenter Studies
Proteins
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma. / Gulmann, Christian; Espina, Virginia; Petricoin, Emanuel; Longo, Dan L.; Santi, Mariarita; Knutsen, Turid; Raffeld, Mark; Jaffe, Elaine S.; Liotta, Lance A.; Feldman, Andrew L.

In: Clinical Cancer Research, Vol. 11, No. 16, 15.08.2005, p. 5847-5855.

Research output: Contribution to journalArticle

Gulmann, C, Espina, V, Petricoin, E, Longo, DL, Santi, M, Knutsen, T, Raffeld, M, Jaffe, ES, Liotta, LA & Feldman, AL 2005, 'Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma', Clinical Cancer Research, vol. 11, no. 16, pp. 5847-5855. https://doi.org/10.1158/1078-0432.CCR-05-0637
Gulmann, Christian ; Espina, Virginia ; Petricoin, Emanuel ; Longo, Dan L. ; Santi, Mariarita ; Knutsen, Turid ; Raffeld, Mark ; Jaffe, Elaine S. ; Liotta, Lance A. ; Feldman, Andrew L. / Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 16. pp. 5847-5855.
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AU - Espina, Virginia

AU - Petricoin, Emanuel

AU - Longo, Dan L.

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AU - Knutsen, Turid

AU - Raffeld, Mark

AU - Jaffe, Elaine S.

AU - Liotta, Lance A.

AU - Feldman, Andrew L

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AB - 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.

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