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M Seto

Publications and source records attributed to M Seto.

At least 127 records · Page 7Linked to original sources
PubMed1997

Chimeric MLL products with a Ras binding cytoplasmic protein AF6 involved in t(6;11) (q27;q23) leukemia localize in the nucleus.

In infantile leukemias and therapy-related leukemias, the MLL gene is frequently found to be disrupted and fused to various translocation partner genes, such as AF4/FEL, LTG9/AF9 and LTG19/ENL as a result of 11q23 translocations. We previously showed that the N-terminal portion common to various chimeric MLL products, as well as to MLL-LTG9 and MLL-LTG19, localizes in the nuclei, and therefore suggested that it might play an important role in leukemogenesis. In the present study, MLL-AF6 chimeric products found in the t(6;11)(q27;q23) translocation were analysed since AF6, a Ras-binding protein, exhibits a different subcellular localization from that of LTG9/AF9 and LTG19/ENL. Immunofluorescence staining data and cell fractionation analyses demonstrated that MLL-AF6 chimeric products localize in the nuclei despite the fact that AF6 itself localizes in the cytoplasm, confirming the importance of the nuclear localization of chimeric MLL products. The region in the N-terminal portion of MLL responsible for this nuclear localization was examined and found to be a region containing AT-hook motifs.

Animals↗
PubMed1997

CD7+ and CD56+ myeloid/natural killer cell precursor acute leukemia: a distinct hematolymphoid disease entity.

The disease spectrum of natural killer (NK) cell leukemias and lymphomas has recently been expanding with the continuing evolution in diagnostic concepts. We describe here seven cases of acute leukemia of conceivable myeloid and NK cell precursor phenotype in six men and one woman varying from 19 to 59 years of age (median, 46 years). Striking extramedullary involvement was evident at initial presentation, with peripheral lymphadenopathy and/or mediastinal masses. Two lacked any leukemic cells in the bone marrow at diagnosis. Using cytochemical myeloperoxidase staining, less than 3% of the leukemic cells showed positive reactivity. However, expression of CD7, CD33, CD34, CD56, and frequently HLA-DR, but not other NK, T-cell, and B-cell markers was observed. Cytoplasmic CD3 was detected in three of the cases by flow cytometry and in six by Northern blotting, suggesting an origin from common progenitors between the NK cell and myeloid lineages. All but one presented germline configurations of the T-cell receptor beta and gamma chain genes and Ig heavy chain gene. With regard to morphology, the cells were generally L2-shaped, with variation in cell size, round to moderately irregular nuclei and prominent nucleoli, pale cytoplasm, and a lack of azurophilic granules. Histopathologic examination of biopsied specimens of extramedullary tumors showed a lymphoblast-like morphology, implying the differential diagnostic problem from lymphoblastic lymphomas, especially in cases lacking bone marrow involvement. Three patients were successfully treated with chemotherapy for acute myeloid leukemia (AML), whereas three other patients proved refractory to chemotherapeutic regimens for lymphoid malignancies, although two responded to subsequent AML chemotherapy. However, despite intensive chemotherapy, including allogeneic bone marrow transplantation, most persued fatal courses within 41 months. These data suggested that the CD7+ and CD56+ myeloid/NK cell precursor acute leukemia might constitute a distinct biologic and clinical disease entity. Its recognition appears to be particularly important for the clinicopathologic evaluation of CD56+ hematolymphoid malignancies and the development of therapeutic approaches to such disease.

Acute Disease↗
PubMed1997

Detection of 14q32.33 translocation and t(11;14) in interphase nuclei of chronic B-cell leukemia/lymphomas by in situ hybridization.

Abnormalities of chromosome 14 involving band q32.33 are among the most commonly observed cytogenetic alterations in B-cell malignancies. To assess the incidence and pathogenetic implications of 14q32.33 translocation in chronic B-cell leukemia/lymphomas, we performed fluorescence in situ hybridization (FISH) analysis with variable region (V(H)) and gamma constant region (Cgamma) gene probes in 37 patients with these disorders. Chromosome 14q32.33 translocation was detected in 2 of 18 patients with chronic lymphocytic leukemia (CLL), 1 of 2 with CLL of mixed cell types (CLL/PL), 1 of 2 with pro-lymphocytic leukemia (PLL), 5 of 6 with leukemic mantle-cell lymphoma (MCL), 2 of 7 with splenic B-cell leukemia/lymphoma of possible marginal zone origin (SBLL) and 2 with leukemic follicular lymphoma (FL). To further characterize 14q32.33 translocations in these patients, we developed a new procedure using double-color FISH with PRAD1, BCL2, V(H) and Cgamma gene probes. Chromosome t(11;14) was detected in 1 patient with CLL/PL, 1 with PLL and 5 with MCL. Chromosome t(14;18) was detected in 2 patients with FL. In a PLL patient with t(11;14), the cosmid CPP29 containing the PRAD1 gene and its 5'-flanking region split and co-localized with both Cgamma and V(H) gene probes, thus spanning the breakpoint. In CLL and SBLL patients, donor chromosomes were other than chromosomes 2, 11, 18 and 19, suggesting the involvement of a novel oncogene(s) in the pathogenesis of these diseases. Interphase FISH rapidly detected 14q32.33 translocation, t(11;14) and t(14;18) in B-cell malignancies with low mitotic activity at the single-cell level, facilitating the correlation of the molecular features of these translocations with clinical characteristics.

Adolescent↗
PubMed1997

Scanning force microscopy of the interaction events between a single molecule of heavy meromyosin and actin.

How close an approach is necessary for two interactive protein molecules to recognize each other before association? How strong a force field is exerted between two proteins at the recognition distance? How extensive are the association interfaces? How strong a force is necessary to pull the associated proteins apart? By means of atomic force microscopy at a truly single molecule level, these fundamental and intriguing questions were answered with the muscle proteins actin and myosin.

Actins↗
PubMed1997

In vitro effects of a recombinant toxin, mSCF-PE40, targeting c-kit receptors ectopically expressed in small cell lung cancers.

Most small cell lung cancers (SCLCs) ectopically express high levels of the c-kit receptor. We have examined if the receptor can serve as a target for a chimeric toxin, mSCF-PE40 composed of murine stem cell factor (SCF) genetically fused to the N terminus of a modified form of Pseudomonas exotoxin (PE) lacking its cell recognition domain. Selective cytotoxicity was found for human c-kit receptor-negative cells. This agent thus warrants further evaluation for therapy of human CSLCs.

ADP Ribose Transferases↗
PubMed1997

Aripiprazole, a novel antipsychotic drug, inhibits quinpirole-evoked GTPase activity but does not up-regulate dopamine D2 receptor following repeated treatment in the rat striatum.

Aripiprazole, a quinolinone derivative, is a new dopaminergic agent which has been recently developed and demonstrated to be clinically useful as an antipsychotic drug with reduced extrapyramidal motor side effects. Here, we found that aripiprazole competed [3H]spiperone binding with a 100-fold higher affinity than [3H]SCH23390 binding, and inhibited the quinpirole-induced facilitation of high-affinity GTPase activity in rat striatal membranes. The effects of chronic administration of aripiprazole and haloperidol on dopamine D2 receptor binding and mRNA level in rat striata were examined by a [3H]spiperone binding assay and a ribonuclease protection assay. Haloperidol induced a significant rise in Bmax of [3H]spiperone binding at 1 mg/kg and in the level of dopamine D2L receptor mRNA at 4 mg/kg. A high dose of aripiprazole (100 mg/kg) only tended to increase the Bmax of [3H]spiperone binding non-significantly, and had no effect on the level of dopamine D2L receptor mRNA. These results indicated that aripiprazole had an antagonistic activity to dopamine D2 receptors with a high affinity, but that the potency of aripiprazole to up-regulate dopamine D2 receptors in the striatum was much smaller than that of haloperidol. This small up-regulation may be related to the ability to aripiprazole to act without side effects including tardive dyskinesia.

Animals↗
PubMed1997

Detection of chimeric mRNAs by reverse transcriptase-polymerase chain reaction for diagnosis and monitoring of acute leukemias with 11q23 abnormalities.

Recurrent translocations involving chromosome band 11q23 are often found in human acute leukemias. Recently, the MLL gene on 11q23 and 10 partner genes involved in these translocations have been cloned and characterized. We performed a reverse transcriptase-polymerase chain reaction (RT-PCR) to detect the resultant der(11) chimeric mRNAs of the 3 types of 11q23 translocations including t(4;11), t(9;11), or t(11;19), in 14 leukemia patients with MLL gene rearrangements. At diagnosis or relapse, chimeric mRNA could be detected in all of the 4 patients with t(4;11), 2 of 3 with t(9;11), 2 of 3 with t(11;19), and 1 of 4 with unsuccessful karyotype. In 5 patients, we could monitor minimal residual disease (MRD) serially through the clinical course. One patient, in whom chi-meric mRNA was detected during complete remission (CR) just after the induction chemotherapy, relapsed within 2 months and died, while 2 patients in which chimeric mRNA was not detected remained in CR from 10-23 months. These findings suggest that RT-PCR is a useful approach for detecting which partner gene is involved in the translocation and monitoring MRD in patients with MLL gene rearrangement. Nonetheless, the clinical relevance of MRD evaluation by RT-PCR monitoring remains controversial. Long-term and prospective investigation of a larger series of patients is needed to confirm the clinical significance of monitoring MRD by RT-PCR method.

Acute Disease↗
PubMed1997

BCL6 rearrangement in a patient with mantle cell lymphoma.

We describe a patient with mantle cell lymphoma (MCL) associated with BCL6 gene rearrangement. MCL is a distinct subtype of non-Hodgkin's lymphoma characterized by CD5+, CD10-, CD20+, t(11;14)(q13;q32) and PRAD1/cyclin D1 overexpression. Although rearrangement of the BCL6 gene is the most frequent genetic change among diffuse lymphomas and some follicular lymphomas this is the first report of a patient with MCL associated with BCL6 rearrangement.

Aged↗
PubMed1997

The role of myosin light chain kinase-dependent phosphorylation of myosin light chain in phorbol ester-induced contraction of rabbit aorta.

We investigated the role of 20 kDa myosin light chain (MLC20) phosphorylation in contractions following protein kinase C (PKC) activation by 12-deoxyphorbol-13-isobutyrate (DPB) in rabbit aortae. DPB induced a sustained contraction and phosphorylation of MLC20 independent of a change in cytosolic Ca2+ ([Ca2+]i). Phosphorylation on Ser19 of MLC20, which is a target site of MLC kinase (MLCK), was 9.2 +/- 5.1% and 22.3 +/- 4.9% of the phosphorylation caused by KCl, at 5 and 30 min of application of DPB, respectively. When KCl-precontracted muscles were rinsed with Ca2+-free, EGTA solution, [Ca2+]i rapidly declined, MLC20 was dephosphorylated and the tension decreased. If DPB was present in the Ca2+-free solution, the relaxation and the dephosphorylation of either total MLC20 or Ser19 were inhibited. The phospholipase A2 inhibitor ONO-RS-082 partially antagonized the effects of DPB on the tension and the MLC20 dephosphorylation. In Ca2+-free solution, DPB induced a contraction smaller than that in normal solution without an increase in MLC20 phosphorylation, and the contraction was also sensitive to ONO-RS-082. These results suggest that a part of MLC20 phosphorylation following PKC activation is due to inhibition of MLC20 phosphatase and the phosphorylation is responsible for the contraction. Furthermore, a mechanism independent of [Ca2+]i and phosphorylation may play a significant role in the PKC-dependent contraction. The involvement arachidonic acid is suggested, not only in the inhibition of dephosphorylation but also in the Ca2+-independent regulation of contractile proteins.

Animals↗
PubMed1997

Complete cytogenetic response with host-derived hematopoiesis induced by cyclosporin A discontinuation in a patient with relapsed chronic myelogenous leukemia after bone marrow transplantation.

A 46-year-old woman with Ph-positive CML received an unmanipulated BMT from an HLA-identical brother, conditioned with busulfan-cyclophosphamide. Five months after BMT, cytogenetic relapse occurred, and CsA was decreased and then discontinued. Mild acute GVHD occurred, but gradually improved with no immunosuppression. Forty days after CsA discontinuation, both cytogenetic and fluorescence in situ hybridization analyses showed a host-derived normal karyotype, 46,XX, and no evidence of leukemic cells or donor graft. The sustained host-derived hematopoiesis lasted for 2 years until sudden recurrence of CML. In this case, the discontinuation of CsA led to GVHD and also suppression of the relapsed leukemia, presumably by a 'specific' GVL effect. There was also graft failure. The observation that subsequent hematologic recovery was of host origin implies that, at least in this case, the GVL effect was not directed against normal host-type hematopoiesis.

Bone Marrow Transplantation↗
PubMed1997

Expression of CD8beta and alteration of cell surface phenotype in adult T-cell leukaemia cells.

Typical adult T-cell leukaemia (ATL) cells have a CD4+ CD8- cell surface phenotype, but atypical phenotypes such as CD4+ CD8+ and CD4- CD8+ have also been reported. The CD8 molecule is composed of alpha and beta chains and commonly used monoclonal antibodies against CD8 molecule detect only CD8alpha. Since it has been reported that CD8alpha can be induced in mature CD4+ T cells by cell activation, but not CD8beta, we studied whether ATL cells which express CD8alpha may also express CD8beta. We found some cases of CD8alpha+ ATL were also positive for CD8beta. Furthermore, we experienced a case whose ATL cell surface phenotype changed from CD4+ CD8alpha+ CD8beta+ to CD4- CD8alpha+ CD8beta+ and finally to CD4+ CD8alpha- CD8beta-. Southern blot analysis revealed that the monoclonal integration of human T lymphotropic virus type I (HTLV-I) was identical throughout the course of the study, indicating that a single clone had demonstrated the alterations. These data suggest that peripheral CD4+ CD8+ ATL cells can express not only CD8alpha, but also CD8beta and that a single ATL cell clone has the potential to change its surface phenotype in vivo as well as in vitro.

Adult↗
PubMed1997

Complementarity determining region-III is a useful molecular marker for the evaluation of minimal residual disease in mantle cell lymphoma.

Bone marrow (BM) and peripheral blood (PB) involvement in 10 patients with mantle cell lymphoma (MCL) was analysed by a polymerase chain reaction (PCR)-mediated RNase protection assay. The complementarity determining regions (CDR)-III of all 10 MCLs examined was amplified efficiently with consensus V(H) and J(H) primers by PCR. and BM and/or PB involvement was evaluated by RNase protection assay in all 10 patients examined. Our assay showed BM and/or PB of the entire group to have neoplastic cells at presentation, despite the fact that eight patients were found to have BM and/or PB involvement on the basis of morphological examination and/or surface marker analysis. We also examined minimal residual disease (MRD) after conventional chemotherapy, and detected MRD in a patient in complete remission (CR). Although previous studies have shown that t(11;14) breakpoint amplification by PCR was only applicable to about 30-40% of cases, the present study indicates that CDR-III is a useful molecular marker and the PCR-mediated RNase protection assay is a good tool for the evaluation of MRD in MCL. It is suggested that BM and PB of MCL patients are quite frequently involved at presentation and even after conventional chemotherapy at the molecular level.

Aged↗
PubMed1997

A nodal gamma/delta T-cell lymphoma with an association of Epstein-Barr virus.

The postthymic gamma/delta T-cell lymphoma is rare, and most occur as extranodal tumors, e.g., in hepatosplenic or cutaneous forms. We here report an unusual nodal case that initially presented as a T-zone lymphoma. The neoplasm recurred as systemic lymphadenopathy 25 months after complete remission with terminal high-grade transformation. Phenotypic analysis showed CD1-, CD2+, CD3+, CD4-, CD5-, CD7+, CD8+, CD10-, CD16-, CD19-, CD20-, CD21-, CD25-, CD56-, CD57-, T-cell receptor (TCR) alpha/beta antigens negative, TCR gamma/delta antigens positive, and an HLA-DR+ phenotype. Cytogenetic studies showed clonal chromosomal translocations involving chromosomes 1, 5, 6, 8, 15, and X in eight of 15 cells; t(X;5;1)(q13;q13;p22) and t(6;15;8)(p22;q26;q13). Genotypic analysis showed the same clone, characterized by the TCR gamma-chain gene rearrangement pattern, to be present in both initial and recurrent tumors. The lymphoma cells were also demonstrated to express the latent membrane protein-1 by immunohistochemistry and EBV-encoded small RNAs by in situ hybridization. Southern blot analysis using the probe of the terminal repeat demonstrated incorporation of multiple copies of EBV in the recurrent tumor. However, the initial lesion, which contained a smaller number of EBV-positive cells, showed no such evidence of clonal proliferation. These data suggest that EBV may be associated with high-grade transformation, although its exact role in lymphomagenesis remains uncertain. The present study also adds to our understanding of the clinicopathologic spectrum of gamma/delta T-cell neoplasia.

Aged↗
PubMed1997

Anaplastic large cell lymphoma: a distinct molecular pathologic entity: a reappraisal with special reference to p80(NPM/ALK) expression.

The p80(NPM/ALK) expression activated by the t(2;5) (p23;q35) translocation recently has been shown to play an important role in the pathogenesis of anaplastic large cell lymphoma (ALCL). However, the clinicopathologic significance of identification of p80 among ALCL cases has not been completely resolved. Difficulties also exist in the histologic and immunophenotypic identification of ALCL and Hodgkin's disease (HD) as separate processes, often complicating the clinicopathologic evaluation of and therapeutic approach to these entities. In order to clarify these issues, 67 specimens of ALCL and 63 specimens of HD (31 of the nodular-sclerosing type [NS-HD] and 32 of the mixed-cellularity type [MC-HD]) were immunostained using anti-p80 antibody and other relevant markers on paraffin sections. The clinicopathologic and immunophenotypic features were reviewed on the basis of p80 reactivity. The expression of p80 was detected in 43 of 67 cases of ALCL (64%), but none of HD. The p80+ ALCL cases constituted a very homogeneous group of tumors, characterized by the occurrence in a much younger group and relatively more favorable clinical course than the p80- ALCL, which were in keeping with the data previously reported. They showed virtually the identical immunophenotypic findings of p80+, CD30+, EMA+, CD15-, bcl-2-, and Epstein-Barr virus (EBV) with T- and null-cell phenotype, and showed the distinct morphologic features, including three cases of lymphohistiocytic/small-cell variant, as follows: the indented nuclei, often termed as reniform, embryolike, and horseshoelike; multiple, irregular, but indistinct nucleoli; and few reactive cells of eosinophils and epithelioid cells. Conversely, the 24 p80- ALCL cases, in which epithelial membrane antigen (EMA) and bcl-2 positivities were 33% and 55%, respectively, were heterogeneous and could be subdivided into five different categories, namely (a) 11 cases of HD-like ALCLs, (b) six cases of p80 common ALCL, (c) three cases of secondary ALCL, (d) two cases of primary cutaneous ALCL, and (e) two cases of primary classical ALCL that lacked p80 expression. This study clearly demonstrated that the immunohistochemical detection of p80 is of a crucial importance in delineating the biologically distinct entity of "primary classical ALCL" from various diseases that show morphologic and immunohistologic overlap, including HD and HD-like ALCL.

Adolescent↗
PubMed1997

Somatic hypermutations in the VH segment of immunoglobulin genes of CD5-positive diffuse large B-cell lymphomas.

De novo CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBL) has recently been identified as constituting a homogeneous subgroup with distinct clinicopathologic and genotypic characteristics, but its origin remains to be elucidated. Previous studies by sequence analysis of the variable region of the immunoglobulin heavy chain (VH) have shown that CD5+ B-cell malignancies such as mantle cell lymphoma (MCL) and B-cell chronic lymphocytic leukemia (B-CLL) cells represent pre-germinal center (pre-GC) stage B cells in contrast with the post-GC stage of most DLBLs, which show somatic hypermutations in VH genes. In the present study, we investigated the VH sequence of de novo CD5+ DLBL to clarify whether CD5+ DLBL represents the pre-GC stage, as do other CD5+ B-cell malignancies, or the post-GC stage, as is typical of DLBL. All eight cases (four CD5+ DLBL and four CD5-negative (CD5-) DLBL) examined by us showed somatic hypermutations in the VH segment and two of the CD5- DLBL cases showed intra-clonal diversity, suggesting that CD5+ DLBLs were derived from the same maturation stage as CD5- DLBL, but were distinct from the other indolent CD5+ B-cell lymphomas of B-CLL and MCL. These data suggest that de novo CD5+ DLBLs do not merely lie within a continuous spectrum with B-CLL and MCL, but represent a biologically distinct variant within the diagnostic framework of diffuse large B-cell lymphoma.

Adult↗
PubMed1997

Clinicopathologic study of nasal T/NK-cell lymphoma among the Japanese.

A high prevalence of nasal lymphoma expressing a T- or natural killer (NK)-cell phenotype (NTCL) with frequent association of Epstein-Barr virus (EBV) has been indicated in Asians. To characterize NTCL among the Japanese, the clinicopathologic features of 32 cases were evaluated and the cases were also analyzed for EBV-RNA using an ISH method. Morphologically, 31 cases were identified by atypical pleomorphic lymphoid infiltrates with polymorphous, angicentric, and necrotic features. Their lymphoma cells ranged in size from small to large and were mixed in varying proportion from case to case. The other one case showed a monomorphic 'blastic' appearance. EBV-encoded small RNA (EBER) was detected in the neoplastic cells of 27 of the 32 cases examined. In the five EBV-negative cases, one was the 'blastic' type. Clonal T-cell receptor gene rearrangement was detected in none of seven cases examined. The patients had a median follow-up of 9 months (range, 1 month to 14 years and 11 months). The Kaplan-Meier estimate of overall survival was 49% at 5 years, correlating with clinical stage. These data support the concept that most cases of NTCL are identified as tumors with T/NK-cell characteristics and EBV association, distinctly different from other peripheral T-cell lymphomas. Furthermore, the one case of an EBV-negative 'blastic' variant appears not to fit well into the pleomorphic category but more closely resembles the pathologic features of extranasal angiocentric lymphoma with lymphoblastoid appearance. This study also showed no clear difference in clinical aspects other than the original site or in prognosis, between NTCL and extranasal angiocentric lymphomas despite the higher incidence of EBV association and the tendency for that peculiar anatomical site to be restricted to the former group.

Adolescent↗
PubMed1997

Cyclin D1 overexpression in malignant lymphomas.

Cyclin D1, the regulatory subunit of certain protein kinases thought to advance the G1 phase of the cell cycle, is now established as a proto-oncogene, with evidence indicating that its derangement may contribute to the uncontrolled cell growth characteristic of tumors. The chromosomal translocation t(11;14)(q13:q32), involving rearrangement of the BCL-1 locus, is closely associated with human lymphoid neoplasia affecting mantle cell lymphomas (MCL). Recently, the putative BCL-1 proto-oncogene turned out to be none other than the cyclin D1 gene. Although the observed break points in the BCL-1 locus are not tightly clustered, its rearrangement has been documented in 40-70% of cases of mantle cell lymphoma, whereas it only rarely occurs in other B cell lymphomas. Of note, all of the known break points leave the cyclin D1 coding region structurally intact and result in increased protein expression, implying that this may provide a highly sensitive and specific marker for MCL. Recent studies demonstrated that immunohistochemical detection in paraffin-embedded material, using a monoclonal antibody, is very useful for routine diagnosis. Current knowledge of cyclin D1 overexpression in malignant lymphomas, with emphasis on its clinicopathologic significance, is reviewed.

Aged↗