ABSTRACT
Jaw1, also known as lymphoid-restricted membrane protein (LRMP), is an endoplasmic reticulum-associated protein. High levels of Jaw1/LRMP mRNA have been found in germinal centre B-cells and in diffuse large B-cell lymphomas of 'germinal centre' subtype. This paper documents Jaw1/LRMP expression at the protein level in human tissues by immunohistochemical and western blotting analysis using an antibody reactive with paraffin-embedded tissues. Jaw1/LRMP was highly expressed in germinal centre B-cells (in keeping with gene expression data), in 'monocytoid B-cells', and in splenic marginal zone B-cells. It was absent, or present at only low levels, in mature T-cells, although cortical thymocytes were weakly positive. Among lymphoid neoplasms, Jaw1/LRMP was found in germinal centre-derived lymphomas (follicle centre lymphoma, Burkitt's lymphoma, lymphocyte-predominant Hodgkin's disease) but not in T-cell neoplasms (with the exception of a single T lymphoblastic lymphoma). Classical Hodgkin's disease and myeloma lacked Jaw1/LRMP but many cases of chronic lymphocytic leukaemia (but not mantle zone lymphoma) were Jaw1/LRMP-positive. Approximately half of the marginal zone lymphomas were Jaw1/LRMP-positive. In diffuse large B-cell lymphomas, Jaw1/LRMP was found in three-quarters (24/32) of the cases classified phenotypically as being of 'germinal centre' type, but it was also expressed in almost half (13/28) of the 'non-germinal centre' cases. A similar proportion of 'non-germinal centre' cases were positive for the protein products of two other genes expressed highly in germinal centre cells (HGAL/GCET2 and PAG). The fact that all three of these proteins are expressed in a significant proportion of diffuse large B-cell lymphomas assigned to the 'non-germinal centre' category indicates that the immunophenotypic categorization of diffuse large B-cell lymphoma according to cellular origin may be more complicated than currently understood. Finally, the expression of Jaw1/LRMP in other types of lymphoma and in non-lymphoid tissues/tumours may be of interest in differential diagnosis and research.
Subject(s)
Biomarkers, Tumor/analysis , Gene Expression Regulation, Neoplastic , Germinal Center/chemistry , Lymphoma, B-Cell/chemistry , Lymphoma, Large B-Cell, Diffuse/chemistry , Membrane Proteins/analysis , Adrenal Glands/chemistry , B-Lymphocytes/chemistry , B-Lymphocytes/ultrastructure , Biomarkers/analysis , Blotting, Western , Cell Line , Cerebral Cortex/chemistry , Epithelial Cells/chemistry , Humans , Immunohistochemistry/methods , Male , Neurons/chemistry , Palatine Tonsil/chemistry , Seminal Vesicles , StomachABSTRACT
Two microarray studies of mediastinal B cell lymphoma have shown that this disease has a distinct gene expression profile, and also that this is closest to the pattern seen in classical Hodgkin's disease. We reported previously an immunohistologic study in which the loss of intracellular B cell-associated signaling molecules in Reed-Sternberg cells was demonstrated, and in this study we have investigated the expression of the same components in more than 60 mediastinal B cell lymphomas. We report that these signaling molecules are frequently present, and in particular that Syk, BLNK and PLC-gamma2 (absent from Reed-Sternberg cells) are present in the majority of mediastinal B cell lymphomas. The overall pattern of B cell signaling molecules in this disease is therefore closer to that of diffuse large B cell lymphoma than to Hodgkin's disease, and is consistent with a common cell of origin as an explanation of the similar gene expression profiles.
Subject(s)
Carrier Proteins/biosynthesis , Enzyme Precursors/biosynthesis , Hodgkin Disease/metabolism , Lymphoma, B-Cell/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , Mediastinal Neoplasms/metabolism , Phosphoproteins/biosynthesis , Protein-Tyrosine Kinases/biosynthesis , Type C Phospholipases/biosynthesis , Adaptor Proteins, Signal Transducing , Blotting, Western , Carrier Proteins/analysis , DNA-Binding Proteins/analysis , DNA-Binding Proteins/biosynthesis , Enzyme Precursors/analysis , Hodgkin Disease/pathology , Humans , Immunohistochemistry , Intracellular Signaling Peptides and Proteins , Lymphoma, B-Cell/chemistry , Lymphoma, B-Cell/ultrastructure , Lymphoma, Large B-Cell, Diffuse/chemistry , Lymphoma, Large B-Cell, Diffuse/pathology , Mediastinal Neoplasms/chemistry , Mediastinal Neoplasms/pathology , NFATC Transcription Factors , Nuclear Proteins/analysis , Nuclear Proteins/biosynthesis , Phospholipase C gamma , Phosphoproteins/analysis , Protein-Tyrosine Kinases/analysis , Signal Transduction , Syk Kinase , Transcription Factors/analysis , Transcription Factors/biosynthesis , Type C Phospholipases/analysis , src-Family Kinases/analysis , src-Family Kinases/biosynthesisABSTRACT
Oncogenic anaplastic lymphoma kinase (ALK) fusion proteins (nucleophosmin-ALK [NPM-ALK] and other variants) are expressed in many cases of anaplastic large-cell lymphoma (ALCL) but are absent from normal tissues. The possibility that ALK proteins are immunogenic was investigated with the use of an immunocytochemical technique to screen plasma from ALK-positive ALCL on transfectants expressing ALK proteins and by an in vitro kinase assay. Circulating antibodies against NPM-ALK protein were present in all ALK-positive ALCL patients (11 out of 11 cases) studied while 10 patients also had antibodies recognizing normal ALK protein. Weak antibodies reactive with NPM-ALK (which may represent anti-NPM autoantibodies) were detected by the in vitro kinase assay in 3 of the 10 control samples (but not by immunocytochemistry). The presence of anti-ALK antibodies may be relevant to the relatively good prognosis of ALK-positive ALCL. The immunocytochemical technique for detecting anti-ALK activity is simple and semiquantative and may provide a means of detecting B-cell responses to other tumor-associated molecules. (Blood. 2000;96:1605-1607)