Expression of serine 194–phosphorylated Fas-associated death domain protein correlates with proliferation in B-cell non–Hodgkin lymphomas

• Published in: Human pathology 2011-08, Vol.42 (8), p.1117-1124
• Main Authors: Drakos, Elias, MD, PhD, Leventaki, Vasiliki, MD, Atsaves, Vasileios, MD, Schlette, Ellen J., MD, Lin, Pei, MD, Vega, Francisco, MD, PhD, Miranda, Roberto N., MD, Claret, Francois-Xavier, PhD, Medeiros, L. Jeffrey, MD, Rassidakis, George Z., MD, PhD
• Format: Article
• Language: English
• Subjects: B cell; Biological and medical sciences; Biomarkers, Tumor - metabolism; Cancer; Cell Count; Cell cycle; Cell Cycle - physiology; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Nucleus - pathology; Cell Proliferation; FADD; Fas-Associated Death Domain Protein - metabolism; Germinal Center - metabolism; Germinal Center - pathology; Hematologic and hematopoietic diseases; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Ki-67 Antigen - metabolism; Kinases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymph Nodes - metabolism; Lymph Nodes - pathology; Lymphadenitis - metabolism; Lymphadenitis - pathology; Lymphoma; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Lymphomas; Medical sciences; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phosphorylation; Phosphorylation, Proliferation; Proteins; Serine - metabolism; Tonsillitis - metabolism; Tonsillitis - pathology; Tumors
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2010.11.002

Summary Fas-associated death domain protein is a key component of the extrinsic apoptotic pathway. In addition, in animal models, Fas-associated death domain protein phosphorylation at serine 194 has been shown to affect cell proliferation, especially in T lymphocytes. The importance of Fas-associated death domain protein phosphorylation at serine 194 for the proliferation of B lymphocytes, however, is uncertain. Here we show in reactive lymph nodes that serine 194 phosphorylated Fas-associated death domain protein is expressed predominantly in the dark (proliferative) zone of germinal centers. In B-cell non–Hodgkin lymphoma cell lines, serine 194 phosphorylated Fas-associated death domain protein levels are substantially higher in highly proliferating cells and lower in serum-starved cells. We also used immunohistochemical analysis to assess Fas-associated death domain protein phosphorylation at serine 194 expression in 122 B-cell non–Hodgkin-type lymphomas. The mean percentage of serine 194 phosphorylated Fas-associated death domain protein positive tumor cells was 81% in Burkitt lymphoma, 41% in diffuse large B-cell lymphoma, 18% in follicular lymphoma, 18% in plasma cell myeloma, 12% in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, 11% in mantle cell lymphoma, and 2% in chronic lymphocytic leukemia/small lymphocytic lymphoma ( P < .0001, Kruskal-Wallis test). Furthermore, in chronic lymphocytic leukemia/small lymphocytic lymphoma, serine 194 phosphorylated Fas-associated death domain protein was detected predominantly in proliferation centers. In the entire study group, the percentage of cells positive for serine 194 phosphorylated Fas-associated death domain protein correlated significantly with the proliferation index Ki-67 (Spearman R = 0.9, P < .0001). These data provide evidence that serine 194 phosphorylated Fas-associated death domain protein is involved in the proliferation of normal and neoplastic B cells and has features of a novel proliferation marker.