title: Expression of serine 194-phosphorylated Fas-associated death domain protein correlates with proliferation in B-cell non-Hodgkin lymphomas.
abstract: 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.
authors.affiliation: Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Drakos
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Leventaki
authors.forename: Vasileios
authors.initials: V
authors.lastname: Atsaves
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Schlette
authors.forename: Pei
authors.initials: P
authors.lastname: Lin
authors.forename: Francisco
authors.initials: F
authors.lastname: Vega
authors.forename: Roberto N
authors.initials: RN
authors.lastname: Miranda
authors.forename: Francois-Xavier
authors.initials: FX
authors.lastname: Claret
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008199:Lymphadenitis / Q000378:metabolism / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D014069:Tonsillitis / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D019394:Ki-67 Antigen; D012694:Serine