Expression of Serine 194-phosphorylated Fas-associated Death Domain Protein Correlates With Proliferation in B-cell non-Hodgkin Lymphomas

Hum Pathol. 2011 Aug;42(8):1117-24. doi: 10.1016/j.humpath.2010.11.002. Epub 2011 Feb 11.

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.

MeSH terms

  • Biomarkers, Tumor / metabolism
  • Cell Count
  • Cell Cycle / physiology*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Cell Proliferation
  • Fas-Associated Death Domain Protein / metabolism*
  • Germinal Center / metabolism
  • Germinal Center / pathology
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / metabolism
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphadenitis / metabolism
  • Lymphadenitis / pathology
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology*
  • Phosphorylation
  • Serine / metabolism*
  • Tonsillitis / metabolism
  • Tonsillitis / pathology

Substances

  • Biomarkers, Tumor
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Ki-67 Antigen
  • Serine