The bcl-2 proto-oncogene was originally identified through the study of the t (14; 18) translocation present in human B cell lymphomas. This translocation juxtaposes the bcl-2 proto-oncogene with the immunoglobulin heavy chain gene locus, resulting in deregulation of bcl-2 gene expression. Bcl-2 is unique among cellular gene products in its ability to enhance lymphoid cell survival by interfering with apoptotic cell deaths, rather than promoting cell proliferation. Neuronal cell death induced by deprivation of neurotrophic factors has also been shown to be inhibited by bcl-2 protein. Bcl-2 protein has been reported by several groups incuding ours, to be present in multiple membrane locations, namely, nuclear outer membrane, endoplasmic reticulum membrane and mitochondrial outer membrane. The bcl-2 gene is expressed in a variety of tissues and cell types in embryos and adults although the expression is somehow restricted in adults. Several biological functions of bcl-2 have been considered, especially selection of lymphoid cells in immune sytem, determining the life span of cells with long life (neuronal cells, crypt epithelial cells in intestines, lymphoid progenitor in bone marrow) and possibly some roles in morphogenesis.
Animal models with a gain- or loss-of-function have proven useful in analyses of gene function. Using homologous recombination in embryonal stem cells, we recently generated mice homologously deleted in the bcl-2 gene. We have also developed some time ago bcl-2 transgenic mice with elevated bcl-2 expression in B or T cells to analyze molecular process of lymphomagenesis. The results obtained form these two sytems were described.

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In this report, we investigated 73 cases of Hodgkin's disease (HD) and 752 consecutive cases of non-Hodgkin's lymphoma (NHL) to demonstrate EBV in the tumor cells by EBER in situ hybridization. For EBV positive cases, expression of EBNA1, EBNA2, LMP1 and P53 gene products were examined immunohistochemically, EBV-serology and prognostic data were also analyzed. EBV was detected in 48 (65.8%) of Hodgkin's disease in the tumor cells. EBV-positive HD showed expression of LMP1 and episomal monoclonality in all 5 cases examined. Among NHL, EBV was detected in 44 (12.0%) of 368 cases with ATL, 36 (31.6%) of 114 cases with T-ML, 18 (6.8%) of 263 cases with B-ML and none of 7 other types (p<0.00001). High prevalent expression of LMP1 (66%) and P53 gene products (80%) and low prevalent expression of EBNA1 and EBNA2 were observed in EBV-positive NHL cases with similar distribution of EBER ISH sporadic and diffuse positive cases. Episomal clonality of EBV were demonstrated in some cases examined. Elevated antibody titer particularly IgA antibodies against VCA and EA, and poor prognosis of EBV positive cases were observed.

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Cepharanthin (Ceph), a complex of biscoclaurine alkaloids, is known to be effective for increasing platelet counts particularly in patients with idiopathic thrombocytopenic purpura (ITP). We investigated the thrombopoietic effect of a high-dose Ceph treatment on thrombocytopenic patients. The morphological changes of the bone marrow in these patients were investigated by light and electron microscopy. The diseases consisted of 7 ITPs, 4 refractory cytopenias (RCs), and 2 aplastic anemias (AAs). The patients were divided into two groups: (1) prednisolone (PSL)+Ceph and (2) Ceph groups. The PSL+Ceph group consisted of 5 ITP and 1 RC-patients. These patients were refractory to prior PSL therapy, and were subsequently given 60mg of Ceph daily in addition to the PSL therapy. The Ceph group consisted of 2 ITP, 3 RC and 2 AA-patients. In the PSL+Ceph group, 5 out of 6 patients showed significant increase in platelet counts after the initiation of additional Ceph treatment. In the Ceph group, 2 RC patients showed slight increase in platelet counts. Thus, the Ceph treatment was found to be effective for increasing platelet counts, particularly when it was combined with the PSL therapy. To investigate the changes of bone marrow cells caused by the Ceph treatment, the bone marrows of the patients in the PSL+Ceph and Ceph groups were examined by light and electron microscopy. The following findings were seen in the bone marrow obtained during the Ceph treatment: Most of the macrophages showed a foam cell appearance. These cells had many vacuoles containing myelin-like structures. Some macrophages also showed remarkable acid phosphatase activity. Megakaryocytes had aggregated glycogen particles in the cytoplasm. These morphological findings were considered to be caused by the Ceph treatment, and they might be related to the mechanisms of thrombopoiesis.

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Nine cases of primary gastric B-cell lymphoma (PGL) and ten cases of primary thyroidal B-cell lymphoma (PTL) were investigated to detect monoclonality of immunogloblin heavy chain (IgH) gene by polymerase chain reaction (PCR). Monoclonal bands could be detected in 5 of 9 cases of PGL and in 8 of 10 cases of PTL using paraffin sections. One case gave polyclonal bands. In this case, large numbers of small lymphocytes were found to infiltrate the tumor. Sequencing of the PCR products in a part of these cases showed the dominant expression of a single rearrangement in monoclonal cases, whereas in polyclonal cases specific single rearrangements were not found. Interestingly, the dominant clone had the same CDR3 region in cases 4 and 6 of PGL. It was suggested that the some specific antigens might participate in oncogenesis of PGL. The application of the method used in the present study may be helpful in routine diagnosis and in pathological research of B-cell lymphomas.

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