Chromosomal translocations affecting band 3q27, where BCL6 gene is located, are among the most common genetic abnormalities in non-Hodgkin's lymphoma of B-cell type (B-NHL). The BCL6 gene encodes a BTB/POZ zinc finger transcription factor, which exerts repressive activity by recruiting corepressor molecules. The 3q27/BCL6 translocation is unique in that it can involve not only immunoglobulin (Ig) genes but also non-Ig chromosomal loci as a partner. To date, around 20 non-Ig partner genes have been identified. As a result of non-Ig ; BCL6 translocations, many types of regulatory sequences of each partner gene substitute for the 5' untranslated region of BCL6, and the rearranged BCL6 comes under the control of the replaced promoter. The introduction of non-Ig ; BCL6 constructs into transformed cells led to high-level Bcl-6 protein expression in the nucleus, while BCL6 mRNA levels in clinical materials of diffuse large B-cell lymphoma (DLBCL) with non-Ig ; BCL6 translocations were unexpectedly low. A comparative study suggested that non-Ig ; BCL6 translocation and a low level of BCL6 mRNA expression are concordant indicators of a poor clinical outcome in cases of DLBCL. The coexistence of a non-Ig ; BCL6 translocation with t(14 ; 18)(q32 ; q21) in a single clone did not significantly affect the clinical features of follicular lymphoma. The pathogenetic and clinical implications of non-Ig ; BCL6 translocations in B-NHL subtypes may not be identical to those of Ig ; BCL6. [J Clin Exp Hematopathol 46(2) : 43-53, 2006]

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Cytokines exert multiple biological functions through binding to their specific receptors that triggers activation of intracellular signaling cascades. The cytokine-mediated signals may produce variable and even opposing effects on different cell types, depending on cellular context that is also dictated by the differentiation stage of the cell. Multiple myeloma (MM) is a monoclonal proliferative disorder of human plasma cells. Myeloma cells appear to include mixed subpopulations in accordance with the expression of their surface antigens, such as CD45. Although interleukin-6 (IL-6) is widely accepted as the most relevant growth factor for myeloma cells, only a few subpopulations of tumor cells, such as CD45⁺ immature cells, proliferate in response to IL-6. The activation of both signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase (ERK) 1/2 is not sufficient for IL-6-induced proliferation of myeloma cells that requires the src family kinase activation associated with a rapid translocation of CD45 to lipid rafts. The CD45 expression renders myeloma cells competent for not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45⁺ myeloma cells dependently upon the circumstantial stimuli. In contrast, in CD45^- myeloma cells highly expressing IL-6 receptor α chain (IL-6Rα), IL-6Rα and insulin-like growth factor (IGF)-I receptors exist on plasma membrane in close proximity, facilitating efficient assembly of two receptors in response to IL-6. The synergistic effects of IL-6Rα on IGF-I receptor-mediated signals provide a novel insight into a Jak-independent IL-6 signaling mechanism of receptor cross talk in human myeloma cells. Furthermore, the signaling cross talk between the cytokine receptor, IL-6Rα/gp130 and the growth factor receptor tyrosine kinase, fibroblast growth factor receptor (FGFR) 3 appears in myeloma cells carrying t(4;14)(p16.3;q32). In this review we propose several mechanisms of the IL-6-induced cell proliferation that is strictly dependent upon the cellular context in myelomas. [J Clin Exp Hematopathol 46(2) : 55-66, 2006]

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We report here the rare case of a family predisposed to adult T-cell leukemia (ATL). Six of seven siblings developed ATL with ages of onset of 77, 48, 60, 64, 72, and 62 years old. Although virological tests for human T-lymphotropic virus type 1 were unavailable for two of the six patients, all were diagnosed with ATL based on their clinical, hematological, and histopathological features. Two of the six patients were tested for HLA haplotypes using fresh blood samples, and both were carriers of the HLA-A^*26 allele known in the southern Japanese population to be susceptible to ATL. This series of genetic traits may help explain the familial predisposition to ATL. [J Clin Exp Hematopathol 46(2) : 67-71, 2006]

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Germinal centers are highly organized anatomic structures essential for the clonal expansion of germinal center (GC) B-cells and associated somatic hypermutation, isotype switching, selection of the high-affinity B-cells (affinity maturation), and elimination of irrelevant or autoreactive clones. The identification of cellular interactions and regulatory mechanisms controlling apoptosis within GCs is essential for a complete understanding of the cellular and molecular dynamics of the GC reaction. We performed a kinetic analysis of the apoptotic activity occurring within GCs of draining lymph nodes of mice immunized with sheep red blood cells (SRBC) after secondary stimulation. The apoptotic activity of GC cells can be divided into three distinct phases : 1) initial phase (within the first days after immunization), 2) reactive phase (from the 5th day to 15th day after secondary immunization), and 3) late phase (after the 15th day). Apoptosis decreased shortly after secondary immunization followed by an increase to peak after an additional 10 days. Finally, apoptosis of GC cells decreased to basal levels. Administration of apoptosis inhibitors decreased the amount of apoptosis during the reactive phase. These results suggest that the reactive phase may be the critical period in which clonal selection and cellular differentiation to antibody forming cells take place. [J Clin Exp Hematopathol 46(2) : 73-82, 2006]

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In this study, we have categorized cord blood CD5⁺ B cells, which were examined using the horseradish peroxidase-colloidal gold double labeling immunoelectron microscopy, into three subtypes based on their morphology and immunohistochemical characteristics. Type 1a cells and type 1b cells (9% and 17% of the CD5⁺ B cells, respectively) had few cytoplasmic organelles, a high nuclear/cytoplasmic (N/C) ratio (0.66 ± 0.03 and 0.58 ± 0.04, respectively), and a low nuclear contour index (NCI) value (1.56 ± 0.30 and 1.50 ± 0.27, respectively), whereas type 2 cells (74% of the CD5⁺ B cells) had a low N/C ratio (0.44 ± 0.11) and a high NCI value (2.05 ± 0.68). Type 2 cells, which had many cytoplasmic organelles, frequently had several uropod-like processes that bound to the gold particles. The N/C ratios clearly showed that there were significant differences among the three types of CD5⁺ B cells (p < 0.01), and between CD5⁺ T cells and the three types of CD5⁺ B cells (p < 0.05). For the NCI values, only type 1b and type 2 cells showed a significant difference (p < 0.05). These findings suggest that type 1a cells are transformed into type 1b cells, and then into type 2 cells. [J Clin Exp Hematopathol 46(2) : 83-88, 2006]

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