Development of a Malignancy-Associated Proteomic Signature for Diffuse Large B-Cell Lymphoma

• Published in: The American journal of pathology Vol. 175; no. 1; pp. 25 - 35
• Main Authors: Romesser, Paul B, Perlman, David H, Faller, Douglas V, Costello, Catherine E, McComb, Mark E, Denis, Gerald V
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.07.2009; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Biomarkers, Tumor - genetics; DNA Fingerprinting - methods; Electrophoresis, Gel, Two-Dimensional; Female; Gene Expression Profiling - methods; Hematologic and hematopoietic diseases; Image Processing, Computer-Assisted; Investigative techniques, diagnostic techniques (general aspects); Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Mass Spectrometry; Medical sciences; Mice; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Proteomics - methods; Regular; Anatomic pathology; Lymphoproliferative syndrome; Proteomics; Development; Diffuse large B cell lymphoma; B cell neoplasm; Malignant hemopathy; Malignancy; Malignant tumor; Cancer
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.2353/ajpath.2009.080707

The extreme pathological diversity of non-Hodgkin’s lymphomas has made their accurate histological assessment difficult. New diagnostics and treatment modalities are urgently needed for these lymphomas, particularly in drug development for cancer-specific targets. Previously, we showed that a subset of B cell lymphoma, diffuse large B cell lymphoma, may be characterized by two major, orthogonal axes of gene expression: one set of transcripts that is differentially expressed between resting and proliferating, nonmalignant cells (ie, a “proliferative signature”) and another set that is expressed only in proliferating malignant cells (ie, a “cancer signature”). A differential proteomic analysis of B cell proliferative states, similar to previous transcriptional profiling analyses, holds great promise either to reveal novel factors that participate in lymphomagenesis or to define biomarkers of onset or progression. Here, we use a murine model of diffuse large B cell lymphoma to conduct unbiased two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomic analyses of malignant proliferating B cells and tissue-matched, normal resting, or normal proliferating cells. We show that the expression patterns of particular proteins or isoforms across these states fall into eight specific trends that provide a framework to identify malignancy-associated biomarkers and potential drug targets, a signature proteome. Our results support the central hypothesis that clusters of proteins of known function represent a panel of expression markers uniquely associated with malignancy and not normal proliferation.