PubMed Health⌕ Search

Biomedical subjects

N Emi

Publications and source records attributed to N Emi.

At least 19 recordsLinked to original sources
PubMed2007

Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD.

Fms-like tyrosine kinase 3 (FLT3) is expressed in hematopoietic progenitor cells. An internal tandem duplication (ITD) of FLT3 (FLT3/ITD) is the most frequent mutation in human adult acute myeloid leukemia (AML). FLT3/ITD contributes to the constitutive activation of FLT3 itself and its downstream signal components, mitogen-activated protein kinase and signal transducers and activators of transcription 5 (STAT5), and enables interleukin (IL)-3-dependent cell lines to grow autonomously. In the present study, we showed the specific association of FLT3/ITD with Lyn, which led to the phosphorylation of Lyn in vivo. We also demonstrated that FLT3/ITD receptors displayed a higher affinity to bind to Lyn than wild-type FLT3 receptors in vitro and that this affinity was relative to the intensity of tyrosil phosphorylation of the receptor. Both treatment with small interfering RNA (siRNA) targeting Lyn and the Src family kinase inhibitor PP2 suppressed the IL-3-independent growth of FLT3/ITD-expressing 32D cells (FLT3/ITD-32D), reducing the constitutive phosphorylation of Lyn and STAT5. PP2 treatment of mice transplanted with FLT3/ITD-32D cells blocked the onset of tumors and decreased the size of established tumors. These results demonstrate that Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD.

Acute Disease↗
PubMed2006

Increased risk for treatment-related mortality after bone marrow transplantation in GSTM1-positive recipients.

Treatment-related mortality (TRM) is a major obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT). A variety of drugs are used in allogeneic HSCT, and a genetic polymorphism in metabolic enzymes could affect the metabolism of drugs and potentially influence TRM. Here, we focused attention on GSTM1 and GSTT1 enzymes, which metabolize chemotherapeutic agents, chemical carcinogens and by-products of oxidative stress and are absent from more than 50% of some populations. To assess the significance of homozygous GSTM1 and GSTT1 gene deletion in HSCT, we analyzed DNA from 373 patients with hematological disease and their HLA-identical unrelated bone marrow donors using PCR. Homozygous GSTM1 and GSTT1 gene deletions were observed in 56 and 45% of patients, respectively, and 57 and 46% of donors, respectively. There was no significant association between GSTT1 polymorphism and any outcome. However, a GSTM1-positive genotype in recipients was significantly associated with higher TRM and lower survival. These results suggest that a GSTM1-null genotype in recipients protects against TRM after allogeneic HSCT. Further studies are needed to elucidate a mechanism of increased risk for TRM in GSTM1-positive recipients.

Adolescent↗
PubMed2006

Different breakage-prone regions on chromosome 1 detected in t(11;14)-positive mantle cell lymphoma cell lines and multiple myeloma cell lines are associated with different tumor progression-related mechanisms.

To better define secondary aberrations that occur in addition to translocation t(11;14)(q13;q32) in mantle cell lymphomas (MCL) and in multiple myelomas (MM), seven t(11;14)-positive MCL cell lines and four t(11;14)-positive MM cell lines were analysed by fluorescence R-banding and spectral karyotyping (SKY). Compared with published data obtained by G-banding, most chromosome aberrations were redefined or further specified. Furthermore, several additional chromosome aberrations were identified. Thus, these cytogenetically well defined t(11;14)-positive MCL and MM cell lines may be useful tools for the identification and characterization of genes that might be involved in the pathogenesis of MCL and MM, respectively. Since MCL and MM were found to have different alterations of chromosome 1, these were investigated in more detail by fluorescence in situ hybridization (FISH) and multicolor banding (MCB) analyses. The most frequently altered and deletion-prone loci in MCL cell lines were regions 1p31 and 1p21. In contrast, breakpoints in MM cell lines most often involved the heterochromatic regions 1p12-->p11, and the subcentromeric regions 1q12 and 1q21. These data are in accordance with previously published data of primary lymphomas. Our findings may indicate that different pathways of clonal evolution are involved in these morphologically distinct lymphomas harboring an identical primary chromosome aberration, t(11;14).

Cell Line, Tumor↗
PubMed2005

Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome.

To clarify the role of fragile histidine triad (FHIT) in hematological malignancies, we examined the methylation status and the expression level of the FHIT gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells in comparison with the methylation of the p15(INK4B) gene. The FHIT methylation was found in 13 of 94 (13.8%) AML and 22 of 40 (55.0%) MDS cases, but not in normal mononuclear cells (MNCs). Both the frequency and density of methylation increased in the advanced-stages MDS and the relapsed AML cases. Although FHIT and p15(INK4B) methylations were not correlated in MDS and AML, increased FHIT methylation at the relapse in AML was associated with p15(INK4B) methylation. The median expression level in AML was significantly higher than in normal MNCs, although the median expression level in those with methylation was significantly lower than in those without methylation. Furthermore, the methylation level at relapse was significantly higher than at diagnosis in AML. These results suggested that FHIT methylation was accumulated through the disease progression of MDS and AML, and the role of the FHIT gene as a tumor suppressor seemed different in AML and MDS.

Acid Anhydride Hydrolases↗
PubMed2005

Identification and frequency of a new HLA-A allele, A*030104.

We here identified a novel HLA-A allele, A*030104, which was found in a Japanese family. The direct sequencing revealed that A*030104 was identical to A*030101 except for a nucleotide substitution of GAG to GAA at codon 63 without an amino acid replacement. The frequencies of A*030104 and A*0301 including A*030104 in Japanese population (n = 22,360) were approximately 0.013 and 0.40%, respectively.

Alleles↗
PubMed2004

Allogeneic myeloablative transplantation for patients aged 50 years and over.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been performed mainly for young patients due to concern about the high incidence of treatment-related mortality (TRM). Recent advances to reduce TRM by using peripheral blood stem cells or nonmyeloablative conditioning regimens have increased the age limit for this procedure, and correctly identifying the indication for transplant is essential for older patients. In this study, we analyzed data from 398 patients aged 50 or over selected from 5147 patients, who received conventional allogeneic HSCT (c-HSCT). Patients aged 50 or older showed inferior outcomes for TRM and overall survival (OS). Mulitivariate analyses confirmed that an age of 50 or over was an independent risk factor for TRM (P<0.0001) and OS (P<0.0001). Among patients aged 50 or older, increasing age remained an adverse factor for OS (P=0.0213). Regimens including total-body irradiation (TBI) correlated with a higher risk of TRM and a lower OS for older patients (P=0.0095 and 0.0303, respectively). These findings indicate that allogeneic c-HSCT should be offered to patients over 50 years only if the increased risk of TRM is acceptable, and that a non-TBI regimen is preferable when the transplant is performed.

Adolescent↗
PubMed2004

Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan.

Despite recent advances, graft-versus-host disease (GVHD) remains the main cause of treatment failure for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Tacrolimus (FK506) has been increasingly used in place of cyclosporine (CSP), and several studies have shown that FK506 reduces the incidence of acute GVHD more effectively than does CSP. However, no survival benefits have been demonstrated, and no established consensus exists on the choice of these immunosuppressive agents. To compare a CSP-based and an FK506-based regimen, we performed a large-scale retrospective study by using the data of 1935 patients who underwent HSCT from HLA-identical sibling donors (SIB-HSCT) and 777 patients who underwent HSCT from unrelated donors (UD-HSCT). For patients undergoing UD-HSCT, FK506 significantly reduced the risk of acute GVHD and treatment-related mortality (TRM) without an increase in relapse, thus improving overall survival (OS) (hazard ratio (HR): 2.20, 95% confidence interval (CI): 1.60-3.04, P<0.0001 for grade II-IV acute GVHD; HR: 1.81, 95% CI: 1.32-2.48, P=0.0003 for TRM; HR: 1.62, 95% CI: 1.23-2.14, P=0.0007 for OS). This superiority of FK506 was not observed in SIB-HSCT cases. These findings indicate that the use of FK506 instead of CSP for GVHD prophylaxis is beneficial for patients undergoing UD-HSCT.

Acute Disease↗
PubMed2004

TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways.

We previously reported the fusion of the TEL gene to the Syk gene in myelodysplastic syndrome with t(9;12)(q22;p12). TEL-Syk fusion transformed interleukin-3 (IL-3)-dependent murine hematopoietic cell line BaF3 to growth factor independence. Here, we investigate the intracellular signal transduction of the stable transfectants. TEL-Syk fusion protein was associated with the p85 subunit of phosphatidyl inositol 3 kinase (PI3-K) followed by the activation of Akt in the absence of IL-3. Vav, phospholipase C-gamma2 and mitogen-activated protein kinase (MAPK) were also constitutively activated. TEL-Syk also activated the signal transducer and activator of transcription 5 (STAT5) in the absence of Janus kinase 2 activation. None of these kinases were phosphorylated in the BaF3 cells transfected with TELDeltaPNT-Syk in which the oligomerization domain of TEL was deleted. Inhibitor analysis showed that the MAPK pathway was important in TEL-Syk-mediated cell proliferation. The immunofluorescence technique revealed that the TEL-Syk fusion protein was located in the cytoplasm. These data suggest that TEL-Syk fusion protein in the cytoplasm leads to the constitutive activation of PI3-K/Akt, MAPK and STAT5 signal pathways, which are closely involved in IL-3-independent cell proliferation of BaF3 cells.

Amino Acid Substitution↗
PubMed2003

Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation.

CMV disease remains a major infectious complication after allogeneic hematopoietic stem cell transplantation (HSCT). To investigate the relationship between CMV antigenemia, treatment with ganciclovir (GCV), and outcome, we retrospectively analyzed 241 consecutive patients at risk for CMV infection who underwent allogeneic HSCT. Antigenemia-guided pre-emptive strategy with GCV was used for all patients. CMV antigenemia developed in 169 patients (70.1%), and CMV disease in 18 patients (7.5%). Multivariate analysis showed that acute GVHD (grades II-IV) was the only risk factor for developing antigenemia, and acute GVHD and advanced age for CMV disease. GCV use, as well as acute GVHD and advanced age, significantly increased the risk for bacterial and fungal infection after engraftment. Those who developed CMV antigenemia had a poorer outcome than those who did not (log-rank, P=0.0269), although the development of CMV disease worsened the outcome with only borderline significance (log-rank, P=0.0526). In conclusion, detection of antigenemia proved to be a poor prognostic factor for HSCT patients, which may be attributed to a combination of factors, including CMV disease itself, the effect of treatment, and a host status that allows for reactivation of CMV. Optimal pre-emptive strategy needs to be determined.

Adolescent↗
PubMed2003

The percentage of myeloperoxidase-positive blast cells is a strong independent prognostic factor in acute myeloid leukemia, even in the patients with normal karyotype.

To examine whether the percentage of myeloperoxidase (MPO)-positive blast cells is useful as a prognostic factor for acute myeloid leukemia (AML), cytochemical analysis of MPO was performed in 491 patients who were registered to the Japan Adult Leukemia Study Group-AML92 study. Patients were divided into two using the percentage of MPO-positive blast (high [>or=50%] and low (<50%)). Complete remission rates were 85.4% in the former and 64.1% in the latter (P=0.001). The overall survival (OS) and the disease-free survival (DFS) were significantly better in the high MPO group (48.3 vs 18.7% for OS, and 36.3 vs 20.1% for DFS, P<0.001, respectively). Multivariate analysis showed that both karyotype and the percentage of MPO-positive blast cells were equally important prognostic factors. The high MPO group still showed a better survival even when restricted to the intermediate chromosomal risk group or the patients with normal karyotype (P<0.001). The OS of patients with normal karyotype in the high MPO group was almost equal with that of the favorable chromosomal risk group. The percentage of MPO-positive blast cells is a simple and highly significant prognostic factor for AML patients, and especially useful to stratify patients with normal karyotype.

Acute Disease↗
PubMed2003

Sustained activation of c-jun-terminal kinase (JNK) is closely related to arsenic trioxide-induced apoptosis in an acute myeloid leukemia (M2)-derived cell line, NKM-1.

High concentrations (greater than 5 microM) of arsenic trioxide (As(2)O(3)) have been reported to be able to induce apoptosis in several malignant cells. We explored cell lines in which apoptosis was induced with a therapeutic concentration (1-2 microM) of As(2)O(3), and found that 1 microM of As(2)O(3) induced apoptosis in the NKM-1 cell line, which was established from a patient with acute myeloid leukemia (M2). Apoptosis induced by 1 microM of As(2)O(3) in NKM-1 cells was accompanied by an increased cellular content of H(2)O(2), a decreased mitochondrial membrane potential (Deltapsim), and activation of caspase-3. C-Jun-terminal kinase (JNK) was activated only in NKM-1 cells and arsenic-sensitive NB4 cells, but not in arsenic-insensitive HL-60 cells. Activation of JNK in NKM-1 was sustained from 6 to 24 h after As(2)O(3) treatment, and preceded changes in cellular H(2)O(2), Deltapsim, and caspase-3 activation. Moreover, addition of a JNK inhibitor reduced the percentage of apoptotic cells after the As(2)O(3) treatment. Taken together, in the M2 cell line NKM-1, 1 microM of As(2)O(3) induced sustained activation of JNK and apoptosis. This finding may provide a basis to select a subgroup other than acute promyelocytic leukemia, which can benefit from As(2)O(3) treatment.

Acute Disease↗
PubMed2001

Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12).

The TEL gene on 12p12-13 is a target for a number of translocations associated with various hematological malignancies. The fusion of the TEL gene to the Syk gene in a patient with myelodysplastic syndrome (MDS) with t(9;12)(q22;p12) is reported. Southern blot analysis of patient bone marrow cells with TEL and Syk gene probes detected rearranged fragments. Anchored polymerase chain reaction identified the Syk gene, a nonreceptor tyrosine kinase, on 9q22 fused downstream of TEL exon 5. The TEL gene was fused in-frame to Syk and produced a fusion protein that was constitutively phosphorylated in tyrosine with dimerization that was mediated by the helix-loop-helix domain of TEL. A TEL-Syk fusion product transformed the murine hematopoietic cell line BaF3 to interleukin-3 growth factor independence. TEL-Syk is a novel transforming protein and leads to the transformation of hematopoietic cells. These data implicate that the rearranged Syk gene is involved in the pathogenesis of hematopoietic malignancies.

Amino Acid Sequence↗
PubMed2001

Novel synthesized trimannose conjugate induces endocytosis and expression of immunostimulatory molecules in monocytic leukemia cells.

Macrophage mannose receptor (MMR) recognizes the pattern of carbohydrates exposed on microorganisms and mediates endocytosis in macrophages. We have synthesized glycoconjugate cationic polymers carrying 3,6-branched alpha-D-mannoside, a trimannose conjugate (TMC) with a high affinity for mannose-specific lectins. Culture with 10 microM TMC for 6 hours induced adhesion and aggregation in NKM-1, a human myelomonocytic leukemia cell line. TMC also stimulated the accumulation of fluorescein isothiocyanate (FITC)-dextran (FITC-DX). This accumulation seemed to be mediated by endocytosis via MMR because mannan, which specifically binds to MMR, inhibited FITC-DX accumulation. Expression of CD14, adhesion molecules, and costimulatory molecules was induced for 24 hours in NKM-1 and in fresh leukemia blasts from 4 patients with acute myeloid leukemia (AML) M4 and M5 subtypes (French-American-British classification). To clarify the binding mechanism, we compared mannose conjugates and a monomer of mannose regarding their effects on endocytosis and enhancement of CD14 and CD86 expression. A polymer of monomannose clusters with a lower affinity for lectins slightly stimulated exdocytosis, whereas a monomer of trimannose had no effect. These findings suggest that concatenation between MMR and TMC may play an important role in the activation of monocytic leukemia cells. TMC may become a good candidate to target MMRs of leukemia cells.

Acute Disease↗
PubMed2001

Novel gene delivery systems: complexes of fusigenic polymer-modified liposomes and lipoplexes.

We have previously developed the succinylated poly(glycidol)-modified liposome which becomes fusigenic under weakly acidic condition. In this report, we describe that complexation of this pH-sensitive, fusigenic liposome with a lipoplex consisting of 3beta-(N-(N',N'-dimethylaminoethane) carbamoyl)cholesterol, dioleoylphosphatidylethanolamine and plasmid DNA gives efficient gene delivery systems. In this study, we prepared the complexes, which are termed SucPG-complexes, with a positively or negatively charged surface by mixing the lipoplex with varying amounts of the SucPG-modified liposomes. The positively charged SucPG-complexes either bearing or not bearing a cell-specific ligand, transferrin, could transfect HeLa cells efficiently. In contrast, the negatively charged complexes hardly transfected the cells when transferrin was not conjugated to them. However, the negatively charged SucPG complexes bearing transferrin exhibited high transfection ability against HeLa and K562 cells, indicating that this gene delivery was achieved through their binding to the cellular receptors. These transferrin-attached, negatively charged complexes retained the high transfection ability in the presence of serum. Thus, this negatively charged complex may be useful as nonviral vectors in vivo.

Blood↗
PubMed2001

Acute promyelocytic leukemia with apparently normal karyotype: molecular findings and response to all-trans retinoic acid.

Acute promyelocytic leukemia (APL) is specifically associated with a reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of a fusion of the retinoic acid receptor-alpha (RARA) gene and the promyelocytic leukemia (PML) gene. However, there are several reports describing APL cases lacking the t(15; 17). Many such cases are those bearing variant translocations involving chromosomes 15 or 17, and those with no chromosomal aberrations have rarely been reported. We have studied a patient with APL showing an apparently normal karyotype which was confirmed by spectral karyotyping (SKY). A submicroscopic PML-RARA fusion was identified by reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescent in situ hybridization (FISH). All-trans retinoic acid (ATRA) was effective as the initial therapy for remission induction and as the reinduction therapy after a relapse. The present study shows the key role of the fusion of PML-RARA in the responsiveness to ATRA as well as in the leukemogenesis of APL.

Antineoplastic Agents↗
PubMed2000

Aberrant expression of HLA-G antigen in interferon gamma-stimulated acute myelogenous leukaemia.

We have analysed the expression of HLA-G in 40 leukaemia samples of various subtypes [seven cases of acute lymphoblastic leukaemia (ALL), 28 cases of acute myelogenous leukaemia (AML), three cases of chronic myelogenous leukaemia (CML) and two cases of chronic lymphocytic leukaemia (CLL)] by flow cytometry using HLA-G-specific monoclonal antibody. No leukaemia samples expressed HLA-G without incubation with interferon (IFN)-gamma. However, six out of 28 (21%) AML samples expressed HLA-G upon incubation with IFN-gamma. These six samples derived from one out of seven M2, two out of eight M4 and three out of five M5. The results indicated that AML cells, especially myelomonocytic leukaemia samples, are capable of expressing the HLA-G molecule.

Case-Control Studies↗
PubMed2000

[The current status and future applications of gene therapy and immunogene therapy for malignant lymphoma].

The present therapy for malignant lymphoma including stem cell transplantation, has been greatly developed. However, treatments still remain ineffective for many patients. Gene therapy is providing new strategies for the treatments of malignant lymphoma. There are three major approaches; 1) killing the tumor cell itself by introducing anti-sense genes against oncogene, tumor suppressor genes or drug-sensitive genes. 2) modifying the immune response by introducing genes that will trigger anti-tumor response or tumor specific genes to antigen presenting cell. 3) decreasing the sensitivity of hemopoietic cells by introducing drug resistance genes. We describe here the current and future applications of gene therapy for malignant lymphoma.

Antibodies, Anti-Idiotypic↗