Shoichi Doi

Rearrangement of the BCL6 gene in B-cell lymphoid neoplasms: comparison with lymphomas associated with BCL2 rearrangement.

We report a series of B‐cell neoplasms with regard to rearrangement of the BCL6 gene on chromosome band 3q27. Southern blot analysis using probes from the major translocation cluster (MTC) region of the BCL6 revealed rearrangement in 21/197 patients (10.7%) with B‐cell neoplasms studied at presentation, and 11/25 patients (44%) first studied at relapse. In non‐Hodgkins lymphoma (NHL) studied at diagnosis, rearrangements of the BCL6 gene were not closely associated with a specific histopathologic subtype but distributed in subcategories in the Working Formulation. The incidence in follicular lymphoma was 12.1%, with significantly higher frequency in mixed and large cell subtypes, and that in diffuse aggressive lymphoma was 14.1%. Comigration analysis using probes from the immunoglobulin genes revealed association of the BCL6 gene with one of the three immunoglobulin loci in 9/25 cases analysed. A comparative study between NHL associated either with BCL2 or BCL6 rearrangement showed that advanced disease and bone marrow involvement were more frequent in BCL2(+) NHL. In contrast, extranodal involvement was more frequently observed in the BCL6(+) NHL. The survival curve of BCL6(+) NHL was characterized by a rapid decline followed by a plateau. Of the total of 32 BCL6(+) patients, six carried both BCL2 and BCL6 rearrangements; five of these six showed clinicopathological properties characteristic of follicular lymphoma, suggesting that the presence of the two genetic abnormalities does not necessarily have synergistic effects on malignant phenotypes. The high level of BCL6 expression in follicular lymphoma cell lines carrying a BCL2 rearrangement suggests that the deregulated BCL2 gene may have an effect on the development of genetic abnormalities of the BCL6 gene. The present study suggests that BCL6 gene rearrangement is primarily involved in large cell lymphoma irrespective of growth pattern of neoplastic cells, and that BCL6(+)BCL2(−) NHL could be curable with modern intensive chemotherapy.

Malignant histiocytosis with rearrangement of the heavy chain gene and evidence of monocyte—macrophage lineage

A unique case of malignant histiocytosis (MH) is reported. Its origin from the monocyte—macrophage system was indicated by expression of highly specific myeloid cell markers (My4, MCS2, and cytoplasmic lysozyme), diffuse activity of acid phosphatase and NaF‐sensitive α‐naphthyl acetate esterase, lack of immunologic markers specific for other cell lineages, and germ line configuration of the immunoglobulin light chain gene and the T‐cell receptor β‐chain gene. Its neoplastic nature was suggested by the single rearranged band of the immunoglobulin heavy chain gene.

A Novel B Cell Line Established from Ki-1-positive Diffuse Large Cell Lymphoma

A novel cell line, designated KIS‐1, was established from a patient with Ki‐1‐positive diffuse large cell lymphoma. Multiple phenotypic analysis of the KIS‐1 cells was carried out with a total of 22 monoclonal antibodies defining hematopoietic cell subsets and lineages. The KIS‐1 cells were positive for Ki‐1, B4, HLA‐DR, and 2D1 (common leucocyte) antigens, but were negative for the antigens reportedly specific for T cells, natural killer cells, granulocytes, monocytes, interdigitating reticulum cells and dendritic reticulum cells. The genomic analysis of the KIS‐1 cells showed not only the rearrangement of JH and Jk genes but also the probable rearrangement of Cγ genes. Moreover, the cells produced immunoglobulin γ chains. Thus, KIS‐1 was considered to be of B‐cell lineage. The lymphoma‐cell derivation of KIS‐1 was based on the following facts. The cytochemical, immunologic, cytogenetic properties and the results of the molecular genomic analysis in the KIS‐1 cells were essentially the same as those of the original tumor cells, and the KIS‐1 cells were negative for Epstein‐Barr virus‐associated nuclear antigen. KIS‐1 is the only known B‐cell line derived from Ki‐1‐positive diffuse large cell lymphoma, and should be useful for defining the biological implications of Ki‐1 antigen.

Involvement of c-myc oncogene in lymphoma cell lines with no detectable chromosome rearrangement of band 8q24☆

Two lymphoma cell lines of B-cell type were established from Japanese patients with diffuse small noncleaved cell lymphoma. Cytogenetic analysis revealed a 14q+ marker chromosome in both cell lines, and a t(8;14)(q24.1;q32.3) seemed most likely to have occurred. The chromosome 8 pair, however, had no abnormalities. Molecular analysis demonstrated c-myc amplification lacking gross rearrangement in one cell line and genetic rearrangement of c-myc at the first intron as well as aberrant sizes of c-myc mRNA in the other cell line. In the latter case, it is possible that a t(8;14)(q24.1;q32.3) was buried in an unrecognized complex translocation. A combination of cytogenetic and molecular studies to determine the precise nature of the 14q32 translocation is discussed.

Treatment and prognosis of low-grade lymphomas. An analysis of patients treated with chemotherapy.

We analyzed 113 cases of low-grade lymphoma including follicular medium-sized cell type, follicular mixed type and diffuse small cell type of B-cell origin in the LSG classification. Diffuse medium-sized cell type of B-cell origin corresponding to diffuse small cleaved cell in working formulation and intermediate lymphocytic lymphoma, both of which are classified in indolent lymphoma by national cancer institute, was excluded because our study showed poor prognosis of this type. Chemotherapy was done as the primary therapy in 89 patients and anthracycline was used in 63 patients. Analysis of survival rate revealed better prognosis of the chemotherapy with anthracycline from 5 -to 10-year survival, although CR ratio was less than that of the chemotherapy without anthracycline. Significant differences in prognosis were found in clinical stage (I vs II), primary sites (nodal vs exnodal), serum LDH (normal vs high) and therapeutic response (CR vs PR). Follicular medium-sized cell type showed almost the same survival as that of diffuse small cell type within 5 years after onset. Ten patients with follicular medium-sized cell type, however, died more than 5 years after onset and all of 4 patints of 10-year survival were under recurrent disease. In contrast, none of patients with diffuse small cell type died after 4-year survival and all of 4 patients of 10-year survival were disease-free. Improvement of long-term survival of follicular lymphoma is a major problem in chemotherapy of low-grade lymphoma, and a more intensive chemotherapy and/or combination with radiotherapy will be necessary in the near future.