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T Motoji

Publications and source records attributed to T Motoji.

At least 37 records · Page 2Linked to original sources
PubMed1999

Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.

Internal tandem duplication of the FLT3 gene and point mutations of the N-RAS gene are the most frequent somatic mutations causing aberrant signal-transduction in acute myeloid leukemia (AML). However, their prognostic importance is unclear. In this study, their prognostic significance was analyzed in 201 newly diagnosed patients with de novo AML except acute promyelocytic leukemia. Three patients had mutations in both genes, 43 had only the FLT3 gene mutation, 25 had only the N-RAS gene mutation, and 130 had neither. These mutations seemed to occur independently. Both mutations were related to high peripheral white blood cell counts, and the FLT3 gene mutation was infrequently observed in the French-American-British (FAB)-M2 type. AML cases with wild FLT3/mutant N-RAS had a lower complete remission (CR) rate than those with wild FLT3/wild N-RAS, whereas the presence of mutant FLT3 did not affect the CR rate. Univariate analysis showed that unfavorable prognostic factors for overall survival were age 60 years or older (P =.0002), cytogenetic data (P =.002), FAB types other than M2 (P =.002), leukocytosis over 100 +/- 10(9)/L (P =.003), and the FLT3 gene mutation (P =.004). However, the N-RAS gene mutation was only a marginal prognostic factor (P =.06). For the subjects under 60 years old, multivariate analysis showed that the FLT3 gene mutation was the strongest prognostic factor (P =.008) for overall survival. The FLT3 gene mutation, whose presence is detectable only by genomic polymerase chain reaction amplification and gel electrophoresis, might serve as an important molecular marker to predict the prognosis of patients with AML.

Acute Disease↗
PubMed1999

Frequent chromosome arm 13q deletion in aggressive non-Hodgkin's lymphoma.

To clarify the role of allelic loss on chromosome arm 13q in lymphomagenesis, we performed fluorescence in situ hybridization (FISH) analysis of a total of 43 primary lymphomas, including both indolent and aggressive non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD), using the specific probes at RB1 and D13S319 loci on the centromeric portion of chromosome arm 13q. Monosomy at either or both RB1 and D13S319 loci was detected in 15 of 43 (35%) lymphomas (14 of 43 cases at RB1 locus and seven of 43 cases at D13S319 locus); the 13q deletion was frequently detected in the aggressive NHLs (40%; 12 of 30 cases) compared with that in indolent NHL (17%; one of six cases) and a subset of HD (29%; two of seven cases). There are only six cases of 43 which have total monosomy 13q14, all aggressive NHL, 14% of total or 20% of this subgroup. In addition, we analyzed the loss of heterozygosity in 15 of the 43 primary lymphoma samples for several polymorphic microsatellite loci (D13S168, RB1 and D13S272) on the chromosome arm 13q, and confirmed the 13q deletion in four of five cases that were positive on FISH analysis. The subchromosomal region frequently altered in lymphoma on 13q14 is the region around RB1 locus and centromeric to D13S319 locus, which is an overlapped region frequently deleted in chronic lymphocytic leukemia. Together, our data indicate that the 13q alterations are present in a variety of types of lymphoma and occur in a significant proportion of aggressive NHLs, suggesting the possible presence of common candidate gene(s) on the 13q14 region, whose alteration may play an important role in the formation or development of a wide variety of mature lymphoid malignancies.

Adult↗
PubMed1999

Selective effect of cyclosporine monotherapy for pure red cell aplasia not associated with granular lymphocyte-proliferative disorders.

Morphological characteristics of lymphocytes and the response to cyclosporine treatment have revealed some unique patients with pure red cell aplasia. Lymphocytes from these patients consisted mainly of non-granulated lymphocytes. All of the patients were successfully managed by cyclosporine monotherapy irrespective of prior treatment. A reduction in lymphocyte mass was not a prerequisite for the remission of pure red cell aplasia, and responses occurred within 1 month from the start of therapy. Clonal T-cell proliferation was detected in four patients, which raised the possibility of idiopathic pure red cell aplasia being associated with a clonal proliferation of T cells. An examination of the lymphocytes in patients with pure red cell aplasia could potentially be used to plan better therapeutic modalities and assess prognosis.

Adult↗
PubMed1998

Inhibition of P-glycoprotein and recovery of drug sensitivity of human acute leukemic blast cells by multidrug resistance gene (mdr1) antisense oligonucleotides.

To overcome the problem of multidrug resistance, we investigated the effectiveness of phosphrothioate antisense oligonucleotides (MDR1-AS) in suppressing multidrug resistance gene (mdr1) expression in drug-resistant acute myelogenous leukemia (AML) blast cells and the K562 adriamycin-resistant cell line K562/ADM. The percentage of cells with the mdr1 gene product P-glycoprotein (P-gp) was decreased from 100% to 26% by 20 micromol/L MDR1-AS in the K562/ADM cells, and from 48.1% to 10.2% by 2.5 micromol/L MDR1-AS in the AML blast cells. Western blot analysis also showed a decrease in the amount of P-gp in the MDR1-AS-treated K562/ADM cells. This effect was specific to MDR1-AS, and not observed with sense or random control oligonucleotides. The expression of mdr1 mRNA in K562/ADM and AML blast cells treated with MDR1-AS was decreased compared with the random control. Intracellular rhodamine retention and [3H]daunorubicin also increased after antisense treatment. Chemosensitivity to daunorubicin increased in MDR1-AS-treated blast cells up to 5.9-fold in the K562/ADM cells and 3.0- to 6.4-fold in the AML blast cells. The expression of mdr1 mRNA derived from colony cells decreased in the MDR1-AS-treated groups. No inhibitory effect of the oligonucleotides on normal bone marrow progenitors was observed. These findings suggest that MDR1-AS is useful to overcome multidrug resistance in the treatment of leukemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Clonal T-cell proliferation causing pure red cell aplasia in chronic B-cell lymphocytic leukaemia: successful treatment with cyclosporine following in vitro abrogation of erythroid colony-suppressing activity.

Clonal T cells that cause pure red cell aplasia were demonstrated in a patient with chronic B-cell lymphocytic leukaemia. The T-cell fraction was enriched by the immunomagnetic method and shown to have T-cell receptor-beta gene rearrangement. Cryopreserved T cells, obtained during the period of anaemia, suppressed autologous erythroid progenitor cell growth from remission marrow. The colony-suppressing activity was markedly improved by the addition of cyclosporine to the culture medium. The patient achieved haematological remission by cyclosporine monotherapy. Cyclosporine treatment may improve erythropoiesis in both a T-cell-dependent and a T-cell-independent manner.

Blotting, Southern↗
PubMed1997

Expression of the MDR1 and MDR3 gene products in acute and chronic leukemias.

We performed immunocytochemistry to detect mdr1 and mdr3 P-glycoproteins (P-gps) in 81 patients with acute and chronic leukemia, using the mdr1 P-gp-specific monoclonal antibody (MoAb) MRK16, and the mdr3 P-gp-specific MDR3M. Immunoreactivity for the mdr1 gene product was positive in 27 out of 81 (33%) patients. Immunoreactivity with the anti-mdr3 P-gp MoAb was positive in 20 out of 81 (25%) patients. Of 54 patients with acute leukemia, 17 (31%) were positive for mdr1 P-gp and 8 (15%) for mdr3 P-gp. A high proportion (60%) of patients with chronic lymphocytic leukemia (CLL) were mdr3 P-gp positive. Of the patients with granular-lymphocyte proliferative disorder (GLPD), a chronic T-cell or natural killer cell leukemia, 8/17 (47%) were positive for mdr1 P-gp and 6/17 (35%) for mdr3 P-gp. Of 23 patients with chronic leukemia (CLL and GLPD), 10 (37%) were positive for mdr1 P-gp and 12 (44%) for mdr3 P-gp. To clarify the function of the mdr3 P-gp, we examined the intracellular rhodamine123 (Rh123) levels of mdr1 P-gp-negative and mdr3 P-gp-positive leukemic cells from patients with acute lymphocytic leukaemia, on the addition of 10 microM cyclosporin A (CyA). The addition of CyA led to significant increases in intracellular Rh123 levels in mdr1 P-gp-negative and mdr3 P-gp-positive leukemic cells. Results of the assay for dye efflux suggested that the mdr3 P-gp has a role in drug resistance, and functional drug-efflux capacity. In 31 acute leukemia patients at initial diagnosis, mdr1 or mdr3 P-gp expression correlated significantly to an outcome of complete remission (CR). In 54 acute leukemia patients, exposure to precytotoxic agents correlated significantly to expression, with a significant higher number of patients mdr1 or mdr3 P-gp positive than negative. In the 54 patients with acute leukemia, mdr1 P-gp expression correlated to mdr3 P-gp expression significantly (p=0.0007). In the 27 patients with chronic leukemia (CLL and GLPD), mdr1 and mdr3 P-gp expression did not correlate to exposure to precytotoxic agents, nor did mdr1 P-gp expression correlate to mdr3 P-gp expression. It may be speculated that precytotoxic agents induced mdr1 and mdr3 P-gp expression in acute leukemia; however, in chronic leukemia, both P-gps were expressed independently of exposure to precytotoxic agents.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1997

Recovery of drug sensitivity by MS-209, a new multidrug resistance-reversing agent, on acute myelogenous leukaemic blasts and K562 cells resistant to adriamycin cell line.

The efficacy of MS-209, a quinoline derivative synthesized as a new multidrug resistance (MDR)-reversing agent, was studied on blast cells from 33 acute myelogenous leukaemia (AML) patients and on the human myelogenous leukaemia K562 cell line resistant to adriamycin (K562/ADM). By the addition of MS-209, the intracellular daunorubicin (DNR) contents which had been found to be low in P-gp-positive AML blasts and in K562/ADM were significantly enhanced to the level of P-gp-negative blasts and that of sensitive K562. The intracellular rhodamine (Rh123) contents also increased in P-gp-positive blasts and K562/ADM cells with MS-209. A leukaemic blast colony assay also demonstrated the effect of MS-209, i.e. a high D10 value for DNR of P-gp-positive blasts was reduced to the D10 level similar to that observed in P-gp-negative blasts by the addition of MS-209. The greater DNR sensitivity reversing effect of MS-209 was observed in blasts with higher P-gp positivity. These findings suggest the potential usefulness of MS-209 in overcoming MDR in AML patients, especially those with high P-gp expression. This study clarified the relationship between the clinical outcome of the patients and the P-gp positivity, intracellular DNR content and DNR drug sensitivity of leukaemic progenitors.

Adult↗
PubMed1996

Up-regulation of telomerase activity in human lymphocytes.

We detected telomerase activity in human lymphocytes obtained from normal donors. Telomerase was up-regulated within 24 h when peripheral blood mononuclear cells were cultured in the presence of phytohemagglutinin. The activity increased gradually over 72 h, then remained stable for 96 h. During this period, cell number and the length of telomeric DNA remained constant. Anti-CD3 monoclonal antibody and Pansolbin also induced telomerase activity. These results demonstrate that telomerase is regulated during lymphocyte activation as cells progress from G0 to S phase. This system is useful for the study of telomerase during carcinogenesis, and in the testing of telomerase-inhibitory drugs.

Cell Division↗
PubMed1996

Growth stimulatory effect of thrombopoietin on the blast cells of acute myelogenous leukaemia.

Thrombopoietin stimulated blast colony formation in 11/20 acute myelogenous leukaemia (AML) patients studied. The FAB subtypes of the blasts responding to thrombopoietin were not restricted to those of the megakaryocyte lineage, but also included M1-M5 AML blasts. The morphology of colony cells produced by megakaryocytic blasts showed megakaryocytoid features, whereas colony cells produced by M1-M5 AML blasts remained myeloblasts. An increase in CD41 was observed in the cells of colonies produced by blasts from the megakaryocyte lineage involving leukaemia and chronic myeloid leukaemia in blastic crisis. Thrombopoietin receptor was observed on leukaemic blasts which formed colonies following incubation with thrombopoietin.

Cell Division↗
PubMed1996

[Acute myelogenous leukemia with ins(21;8) expressing AML-1-MTG8 fusion transcript].

Here we report a case of acute myelogenous leukemia (M2, FAB classification) presenting with cytogenetic abnormalities of ins(21;8), +del(8) without t(8;21). A 8;21 chromosome translocation is frequently found in acute myelogenous leukemia, especially in the M2 subtype. The translocation results in a fusion transcript between AML1 and MTG8 (ETO), assigned on chromosomes 21 and 8, respectively. Among patients with a t(8;21) abnormality, solid leukemic tumor deposits outside the marrow or good response to chemotherapy are observed frequently. Decrease in neutrophil alkaline phosphatase score and positive rate, and eosinophilia in bone marrow or the blast cells with Auer rods expressing CD19, CD56 antigens occur at a relatively high rate. Although our case lacked these clinical, cytological and cytochemical features, expression of chimeric AML1-MTG8 mRNA was detected. AML1-MTG8 fusion transcript may play a critical role in leukemogenesis of AML M2. Studies on this case may help to reveal the oncogenic function of the AML1-MTG8 fusion gene in AML M2.

Adult↗
PubMed1996

[Polycythemia vera progressing to acute lymphoblastic leukemia after 13 years].

A 54-year-old woman with leukocytosis, was referred to our clinic in February 1982. Based on findings of pancytosis, high NAP score, high serum vitamin B12, increase in total red cell volume and splenomegaly, she was diagnosed as having polycythemia vera (PV). Since then, she has been treated with pipobroman, hydroxycarbamide and phlebotomy. Leukocytosis with increase in blastic cells and thrombocytopenia was noted in August 1995, and she was admitted to our hospital. Since the blastic cells were CD10(+)19(+)20(+), she was diagnosed as having acute lymphoblastic leukemia and treated with vincristine and prednisolone, resulting in remission. This case suggests that PV is a disease of multipotent stem cells including those with a lymphoid lineage.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Mutations of the p53 gene in myelodysplastic syndrome and overt leukemia.

We analysed p53 mutations in 24 patients with myelodysplastic syndrome (MDS) and overt acute myeloid leukaemia after a period of MDS, using polymerase chain reaction-single strand conformation polymorphism analysis. In exons 5 to 8, mobility shifts were detected in five of the 24 patients. Sequence analysis was subsequently performed, and four missense mutations (16.7%) and one silent nucleotide substitution were identified. Patients harbouring mutations were characterized as having advanced disease. Loss of the wild type allele was observed in three of the four patients with missense mutations. No mobility shifts of the N-ras or FMS gene were detected in these four patients. We next analysed the correlation of the p53 mutations with the progression of MDS in three patients. The mutation was accompanied by the progression in two of the three patients. These findings suggest that mutations of the p53 gene are associated with progression in some cases of MDS, while being compatible with stable disease or clonal evolution in others.

Base Sequence↗
PubMed1995

Telomeric DNA in normal and leukemic blood cells.

We studied telomeric DNA in leukemic cells as well as in normal T cells, B cells, monocytes, polymorphonuclear leukocytes, and bone marrow hematopoietic progenitor cells. No marked differences were observed in the sizes of the telomeric repeats in the various populations of normal blood cells obtained from donors in their twenties to sixties, and the telomere length ranged between 8.5 and 9.0 kb. The leukemic cells of 12 patients with acute leukemia (seven with myeloid and five with lymphoid leukemia) showed a variable reduction in the length of telomeric DNA, ranging from 2.7 to 6.4 kb. The average telomere length was 4.8 and 4.7 kb in myeloid and lymphoid leukemia, respectively, while the telomere length in peripheral blood mononuclear cells obtained from the same patients during complete remission was 8.5 and 7.9 kb, respectively. When the same Southern blots were hybridized with Alu or alphoid sequences, no marked changes in the sizes of the repetitive DNA sequences were observed, indicating that the DNA abnormality in the leukemic cells was specific to the telomere region. Investigation of telomeric DNA changes may be helpful in determining the biological properties of leukemic cells.

Adult↗
PubMed1995

Abolition of suppressive effect of acute myeloid leukemia cells on normal granulocyte-macrophage colony formation induced by interleukin-5 associated with eosinophilic cell induction.

The effects of recombinant interleukin-5 (rIL-5) on leukemic blasts obtained from 22 acute myeloid leukemia (AML) patients were investigated. Recombinant IL-5 stimulated leukemic colony formation in the leukemic blasts of 50% of the patients (11/22), and in 7 of these 11 cell cultures leukemic eosinophilic colonies were induced. Eosinophilic cell induction was associated with cellular proliferation, that is, colony or cluster formation. Leukemic blasts cultured with rIL-5 and forming eosinophilic colonies no longer suppressed normal granulocyte-macrophage colony formation, suggesting that functional differentiation of these leukemic blasts took place. Induction of this type of functional differentiation of leukemic blasts may be of clinical value in promoting normal hematopoiesis.

Acute Disease↗
PubMed1994

[Nasal NK-cell lymphoma].

A 75-year-old man was admitted to our hospital on June 1st, 1993, because of nasal obstruction, epistaxis, fever, night sweats and weight loss. Examination disclosed a 2-cm white necrotic mass in the nasal septum, and a biopsy disclosed non-Hodgkin's lymphoma, diffuse, mixed-type. Imprint smears showed cytoplasmic azurophilic granules in the tumor cells. Dense granules were demonstrated by electron microscopy. The tumor cells were CD1-2+3-4-7+8-16+56+57-, and T cell receptor genes were in germline configuration. NK activity against K562 was strongly positive. Based on morphologic, phenotypic, immunogenotypic, and cytotoxic findings, the tumor cells seemed to be derived from activated NK cells. Because the tumor cells were positive for the EB virus and CD21 antigen, EB virus seemed to have infected CD21-positive NK cells and transformed them. MDR P-glycoprotein was also positive. This finding may explain why nasal lymphomas are resistant to chemotherapy and have a poor prognosis.

Cell Transformation, Viral↗
PubMed1993

A bispecific antibody enhances cytokine-induced killer-mediated cytolysis of autologous acute myeloid leukemia cells.

An anti-CD3 Fab' x anti-CD13 Fab' bispecific antibody (BsAb) was generated. This BsAb reacted with both CD3+ T cells and CD13+ acute myeloid leukemia (AML) cells. We investigated whether cytokine-stimulated peripheral blood mononuclear cells (PBMC) could lyse patient AML cells after addition of the BsAb. When interleukin-2 (IL-2)-stimulated PBMC were assayed for their cytotoxicity against 51Cr-labeled allogeneic and autologous CD13+ AML cells, their activity was markedly enhanced by the addition of the BsAb. PBMC stimulated with IL-2 plus anti-CD3 monoclonal antibody (MoAb) showed higher proliferative ability and higher cytotoxicity if this was expressed as lytic units per culture. IL-7-stimulated PBMC also exhibited enhanced cytotoxicity against CD13+ AML cells after addition of the BsAb. Ultrastructurally, CD13+ AML cells incubated with IL-2 plus anti-CD3 MoAb-stimulated PBMC and the BsAb showed apoptotic morphologic changes. A colony assay for AML blast progenitors showed that the colony formation of CD13+ AML cells was inhibited by the addition of autologous IL-2 plus anti-CD3 MoAb-stimulated PBMC, and that this inhibition was further enhanced by the addition of the BsAb. A colony assay for normal bone marrow progenitor cells showed that the addition of autologous IL-2 plus anti-CD3 MoAb-stimulated PBMC and the BsAb inhibited the formation of granulocyte-macrophage colonies and mixed-cell colonies. However, the degree of inhibition was smaller than that for the AML blast colonies. Taken together, these findings suggest that this BsAb may be useful for ex vivo purging of CD13+ AML cells in autologous bone marrow transplantation.

Antibodies, Monoclonal↗
PubMed1993

The effects of leukemia inhibitory factor and interleukin 6 on the growth of acute myeloid leukemia cells.

The effects of leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) on blast progenitors from acute myeloblastic leukemia (AML) were examined using a blast colony assay in a serum-free culture system. LIF and IL-6 stimulated colony growth in 2 and 5, respectively, of 11 cases studied. The simultaneous addition of LIF with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3) or IL-6 produced a statistically significant increase of colony numbers in 3, 6 and 7 of 11 cases, respectively. Numbers of colonies increased significantly when IL-6 was added simultaneously with GM-CSF or IL-3 in 5 and 4 of 11 cases, respectively. LIF or IL-6 used in the primary culture did not significantly change the numbers of secondary colonies compared to GM-CSF. Previous exposure to LIF and IL-6 did not alter cellular phenotype or morphology, indicating that LIF and IL-6 did not induce the differentiation of fresh AML blasts.

Adult↗