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Etsuro Ito

Publications and source records attributed to Etsuro Ito.

At least 19 recordsLinked to original sources
PubMed2026

Polycomb repressive complex 2 insufficiency underlies myeloid leukemia in Down syndrome.

Children with Down syndrome (DS) have an elevated risk of developing myeloid leukemia (ML; ML in DS [ML-DS]). In addition to mutations in GATA1, which generate the truncated isoform GATA1-short (GATA1s), ML-DS requires additional somatic gene mutations, most frequently in cohesion and Polycomb repressive complex 2 (PRC2) genes. Here, we show that PRC2 insufficiency underlies ML-DS pathogenesis. Transplantation of Gata1s fetal liver cells followed by deletion of the cohesion subunit Stag2 and/or the PRC2 component Ezh2 induced megakaryocyte-biased differentiation and expansion of megakaryocytic progenitors, culminating in lethal myelofibrosis. Mechanistically, loss of Stag2 or Ezh2 reinforced Gata1s-driven reduced chromatin accessibility at erythroid transcription factor target loci in premegakaryocyte/erythroid progenitors (pre-MegEs), thereby promoting megakaryocytic skewing. Ezh2 loss attenuated the Gata1s-mediated global elevation of H3K27 trimethylation in pre-MegEs, resulting in derepression of a broad set of PRC2 target genes and establishing a functionally PRC2-insufficient state. Similarly, Stag2 loss induced a moderate but significant degree of PRC2-insufficient state in Gata1s progenitors. Furthermore, chromosome 21-encoded miR-125b blocked megakaryocytic differentiation of Gata1s progenitors lacking either Stag2 or Ezh2 alone but drove full transformation and expansion of CD150+Sca-1+c-Kit+ leukemic stem cell-like populations only upon concurrent loss of both Stag2 and Ezh2, leading to acute megakaryoblastic leukemia in mice. These findings reveal that cohesin and PRC2 insufficiencies converge on PRC2 dysfunction while exerting distinct epigenetic effects and synergize with trisomy 21 and GATA1s to remodel the epigenetic landscape, driving progression from a preleukemic state to overt leukemia.

Animals↗
PubMed2003

Dual regulation of LIM kinase 1 expression by cyclic AMP and calcium determines cofilin phosphorylation states during neuritogenesis in NG108-15 cells.

The present study was designed to elucidate the cellular and molecular mechanisms of neuritogenesis in differentiating neurons. For this purpose, we used pharmacological and immunochemical techniques to determine the intracellular signal transduction pathways that regulate actin dynamics during neuritogenesis. We confirmed that a rise in intracellular cyclic AMP (cAMP) concentration stimulated cells to increase their neurite numbers, and that this increase of neurites was suppressed by activation of calcineurin induced by a Ca2+ influx through voltage-dependent Ca2+ channels. Expression of a specific cofilin kinase (LIM kinase 1) was increased and decreased by cAMP and Ca2+ cascades, respectively. The phosphorylation state, but not the level of expression, of a potent regulator of actin dynamics (cofilin) was strongly correlated with the expression level of LIM kinase 1. Our results suggest that polymerization and depolymerization of actin by cofilin phosphorylation is necessary for neuritogenesis in differentiating neurons.

Actin Depolymerizing Factors↗
PubMed2003

B-cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs.

The transcription factor Bach2, a member of the CNC family of proteins, binds to the Maf recognition element (MARE) by forming homodimers or dimerizing with small Maf transcription factors. Bach2-expressing cells show reduced proliferation and undergo spontaneous cell death. The inhibition of BCR/ABL tyrosine kinase activity by STI571 in chronic myeloid leukemia (CML) cell lines and CD34+ cells from patients with CML in lymphoid crisis results in induction of BACH2 expression. We show here that BACH2 modifies the in vitro cytotoxicity of anticancer drugs. The cytotoxic effects of commonly used anticancer agents were studied by overexpression of BACH2 in RAJI lymphoid cells, a cell line that does not express endogenous BACH2. Cell growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Clones overexpressing BACH2 were more sensitive to etoposide, doxorubicin, and cytarabine than control RAJI cells, whereas there were no significant differences in the sensitivity of either cells to methotrexate or vincristine. Interestingly, we found that the former drugs were oxidative stressors that induced the nuclear accumulation of BACH2. In contrast, methotrexate or vincristine did not induce production of intracellular reactive oxygen species (ROS) and nuclear accumulation of BACH2. These results, coupled with our previous data showing that BACH2 promotes oxidative stress-induced cell death, suggest that combination chemotherapy involving STI571 and anticancer drugs that produce ROS may be of benefit in the treatment of Philadelphia chromosome 1 (Ph1)-positive leukemia.

Active Transport, Cell Nucleus↗
PubMed2003

Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome.

Transient myeloproliferative disorder (TMD) is a leukemoid reaction occurring occasionally in Down syndrome newborn infants. Acute megakaryocytic leukemia (AMKL) develops in approximately 20% to 30% of the cases with TMD. Recently, acquired mutations in the N-terminal activation domain of the GATA-1 gene, encoding the erythroid/megakaryocytic transcription factor GATA-1, have been reported in Down syndrome-related AMKL (DS-AMKL). To understand the multistep leukemogenesis in Down syndrome, GATA-1 mutations were investigated in patients with TMD. We show here that mutations in the GATA-1 gene were detected in 21 of 22 cases with TMD. Most of the mutations in TMD were located in the regions including exon 2 and were essentially identical to those observed in DS-AMKL. In the DS-AMKL cell line, MGS, which itself expresses only a truncated mutant of GATA-1, expression of full-length GATA-1 induced the differentiation toward the erythroid lineage. However, expression of the short form of GATA-1 did not induce erythroid differentiation. These results indicate that expression of GATA-1 with a defective N-terminal activation domain contributes to the expansion of TMD blast cells and that other genetic changes contribute to the development of AMKL in Down syndrome.

Age Factors↗
PubMed2003

Early treatment with oral immunosuppressants in severe proteinuric purpura nephritis.

Nine Japanese children with severe proteinuric Henoch-Schönlein purpura nephritis (HSPN) received prompt initiation of oral prednisolone (1.5 mg/kg/day) combined with an 8-week course of cyclophosphamide (2 mg/kg/day) therapy. All underwent renal biopsy before and after treatment. At presentation, urine protein excretion and histologic indices of the mean activity index, the mean chronicity index and the tubulointerstitial (TI) scores in the patients were 5.0+/-1.4, 4.7+/-1.0, 3.9+/-1.6 and 3.7+/-0.5 g/day, respectively. Urine protein excretion, the activity index and the TI scores decreased significantly at the second renal biopsies obtained at a mean interval of 23 months after the first [0.3+/-0.3, 2.4+/-0.5 and 1.4+/-0.7 g/day ( P<0.01), respectively], while the chronicity index did not change. At the latest observation (mean interval 78 months), all except two showed negative proteinuria while no patient showed renal impairment. Although this case series is without controls, our experience suggests that early treatment with oral prednisolone and cyclophosphamide may be beneficial to a proportion of patients with severe proteinuric HSPN.

Adolescent↗
PubMed2003

Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement.

The possible involvement of germline mutation of the ataxia telangiectasia mutated (ATM) gene in childhood acute leukemia with mixed lineage leukemia (MLL) gene rearrangement (MLL(+)) was investigated. Of the 7 patients studied, 1 showed a germline missense ATM mutation (8921C>T; Pro2974Leu), located in the phosphatidylinositol-3 (PI-3) kinase domain. In reconstitution assays, the ATM mutant 8921T could only partially rescue the radiosensitive phenotype of AT fibroblasts, and in an in vitro kinase assay, it showed a defective phosphorylation of p53-Ser15. Furthermore, the introduction of 8921T in U2OS cells, characterized by a normal ATM/p53 signal transduction, caused a significant reduction of in vivo p53-Ser15 phosphorylation, suggesting a dominant-negative effect of the mutant ATM over the wild-type protein. Our finding in this patient suggests that altered function of ATM plays some pathogenic roles in the development of MLL(+) leukemia.

Ataxia Telangiectasia↗
PubMed2003

Mutations and aberrant DNA methylation of the PROX1 gene in hematologic malignancies.

The homeobox gene PROX1 is related to the Drosophila prospero gene, which is expressed in the developing central nervous system and lens-secreting cone cells. We found that the PROX1 gene had missense and nonsense mutations in 4 of 29 hematologic cell lines analyzed. Decreased mRNA expression was also observed in half of these cell lines by RT-PCR. The restoration of PROX1 gene expression after treatment with the demethylating agent 5-aza-2'-deoxycytidine, as well as bisulfite sequencing analysis, indicated that gene silencing is caused by DNA hypermethylation at intron 1. Such hypermethylation was also seen in primary lymphomas (56.3%, 18/32) in a tumor-specific manner. These findings indicate that the profile of the PROX1 gene corresponds to that of a candidate tumor-suppressor gene.

Azacitidine↗
PubMed2003

Transcriptional profiling in hepatoblastomas using high-density oligonucleotide DNA array.

Hepatoblastoma is a common hepatic tumor in children. Although evidence regarding cytogenetic and molecular genetic alterations in hepatoblastomas has been reported, the molecular events affecting the biologic characteristics of this tumor, including alterations of the gene expression profile, are largely unknown. To identify genes differentially expressed between nondiseased liver (NDL) and hepatoblastoma tumor (HBT), we analyzed the gene expression profile in 14 NDL and 16 HBT samples using a high-density oligonucleotide DNA array. Using Mann-Whitney U test followed by the k-nearest neighbor algorithm, we identified 26 genes (predictor genes) that were able to assign unknown samples derived from NDL and HBT to either the NDL group or HBT group with 100% accuracy. Using a cross-validation approach, we confirmed that the k-nearest neighbor algorithm assigned the particular samples derived from NDL and HBT to either the NDL or HBT group with 93.3% (28/30 samples) accuracy. In the 26 predictor genes, we found alteration of the expression of genes regulating cell division (NAP1L1, STMN1, CCNG2, and CDC7L1) and tumor cell growth (IGF2 and IGFBP4) in HBT. Four predictor genes (ETV3, TPR, CD34, and NR1I3) were also found to be mapped to the chromosomal region 1q21 approximately q32, which has been reported to be frequently involved in the development of hepatoblastoma. The findings obtained in this study suggest that alteration of the expression of some genes regulating cell division and tumor cell growth may be characteristics of the gene expression profile in HBT, and that alteration of the expression of the four predictor genes mapped to chromosomal region 1q21 approximately q32 may also contribute to the differences in gene expression profile between NDL and HBT.

Child↗
PubMed2003

Successful treatment of acute myelomonocytic leukaemia with NUP98-HOXD11 fusion transcripts and monitoring of minimal residual disease.

Patients with haematological malignancies involving the NUP98 gene have been reported to have an aggressive clinical course and a poor outcome. We report successful treatment of a 15-year-old Japanese boy with acute myelomonocytic leukaemia having t(2;11)(q31;p15) and a novel fusion transcript, NUP98-HOXD11. He achieved complete remission by combined chemotherapy, and underwent unrelated cord blood transplantation 4 months after diagnosis. He is in complete remission 24 months after diagnosis. Monitoring of minimal residual disease (MRD) showed the absence of fusion transcript 12 months after transplantation. This is the first report of monitoring MRD in a patient with haematological malignancy involving NUP98 fusion transcripts.

Adolescent↗
PubMed2003

Theoretical research on structures of gamma-aminobutyric acid and glutamic acid in aqueous conditions.

Even though glutamic acid contains only one more carboxyl group than gamma-aminobutyric acid (GABA), these neurotransmitters are recognized by their own specific receptors. To understand the ligand-recognition mechanism of the receptors, we must determine the geometric and electronic structures of GABA and glutamic acid in aqueous conditions using the ab initio calculation. The results of the present study showed that the stable structure of GABA was the extended form, and it attracted both cations and anions. Glutamic acid only attracted cations and was stabilized in four forms in aqueous conditions: Type 1 (an extended form), Type 2 (a rounded form), and Types 3 and 4 (twisted forms of Type 1). The former two types had low energy and the energy barrier between them was estimated to be small. These results showed that most free glutamic acid is present as Type 1, Type 2, and transient forms. The present results therefore suggest that the flexibility of the geometric structures of ligands should be taken into account when we attempt to elucidate the mechanism of recognition between ligands and receptors, in addition to the physicochemical characteristics of ligands and receptors.

Glutamic Acid↗
PubMed2002

Aberrant DNA methylation of p57(KIP2) gene in the promoter region in lymphoid malignancies of B-cell phenotype.

The cyclin-dependent kinase inhibitor p57(KIP2) is thought to be a potential tumor suppressor gene (TSG). The present study examines this possibility. We found that the expression of p57(KIP2) gene is absent in various hematological cell lines. Exposing cell lines to the DNA demethylating agent 5-aza-2'-deoxycytidine restored p57(KIP2) gene expression. Bisulfite sequencing analysis of its promoter region showed that p57(KIP2) DNA was completely methylated in cell lines that did not express the p57(KIP2) gene. Thus, DNA methylation of its promoter might lead to inactivation of the p57(KIP2) gene. DNA methylation of this region is thought to be an aberrant alteration, since DNA was not methylated in normal peripheral blood mononuclear cells or in reactive lymphadenitis. Methylation-specific polymerase chain reaction analysis found frequent DNA methylation of the p57(KIP2) gene in primary diffuse large B-cell lymphoma (54.9%) and in follicular lymphoma (44.0%), but methylation was infrequent in myelodysplastic syndrome and adult T-cell leukemia (3.0% and 2.0%, respectively). These findings directly indicate that the profile of the p57(KIP2) gene corresponds to that of a TSG.

Cyclin-Dependent Kinase Inhibitor p57↗
PubMed2002

Non-ocular dermal photoreception in the pond snail Lymnaea stagnalis.

Based on the results of previous behavioral experiments, researchers believe that sensitivity to light stimuli is not restricted to the eyes in the pond snail Lymnaea stagnalis. To determine the presence of a non-ocular dermal photoreception system and to examine the synaptic connections between this peripheral system and the central nervous system, we electrophysiologically examined the activities of the pedal nerves in L. stagnalis by light stimulation. The results demonstrated that light stimulation evokes non-ocular dermal photosensitive responses in the foot, that these responses exert inhibitory, afferent influences through the inferior pedal nerves to the pedal ganglia, and that these responses were independent of the ocular photoreception system in L. stagnalis.

Action Potentials↗
PubMed2002

Rapidly progressive, pauci-immune diffuse crescentic glomerulonephritis in an infant.

A Japanese male infant presented with nephrotic syndrome at 41 days. His renal function progressively deteriorated, and he died at 4 months of the age. An open renal biopsy revealed diffuse crescentic glomerulonephritis (CrGN) without immune complex deposition, which is not characteristic of the congenital nephrotic syndrome (CNS). Examination for nephrin antigen using rabbit anti-nephrin extra- and intracellular site antibodies was positive. These clinical observations suggest that the patient had a unique histological variant of CNS. This is the first report of rapidly progressive, pauci-immune diffuse CrGN in infancy.

Disease Progression↗
PubMed2002

Activation of Maf/AP-1 repressor Bach2 by oxidative stress promotes apoptosis and its interaction with promyelocytic leukemia nuclear bodies.

The oxidative stress response operates by inducing the expression of genes that counteract the stress. We show here that the oxidative stress-responsive transcription factor Bach2 is a generic inhibitor of gene expression directed by the 12-O-tetradecanoylphorbol-13-acetate response element, the Maf recognition element, and the antioxidant-responsive element. The Bach2-enhanced green fluorescent protein bicistronic retrovirus was used to monitor the fate of Bach2-expressing cells at the single cell level. Bach2 exerted an inhibitory effect on NIH3T3 cell proliferation and caused massive apoptosis upon mild oxidative stress in both NIH3T3 and Raji B-lymphoid cells. Interestingly, Bach1, a highly homologous protein, could not induce cell death, demonstrating the specificity for the apoptosis induction. Although both oxidative stress and leptomycin B, an inhibitor of nuclear export, induce nuclear accumulation of Bach2, the leptomycin B-induced nuclear accumulation of Bach2 was not sufficient to elicit apoptosis. Upon oxidative stress, Bach2 formed nuclear foci that associated with promyelocytic leukemia nuclear bodies. Our results suggest that Bach2 constitutes a cell lineage-specific system that couples oxidative stress and cell death and that inhibition of 12-O-tetradecanoylphorbol-13-acetate response element, the Maf recognition element, and the antioxidant-responsive element upon oxidative stress may be critical determinants for apoptosis.

3T3 Cells↗
PubMed2002

Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan.

PURPOSE: To determine the usefulness of 6-month screening for neuroblastoma. PATIENTS AND METHODS: The cumulative incidence rates (IRs) and cumulative mortality rates (MRs) of neuroblastoma in children younger than 60 months of age were analyzed for control (n = 713,025), qualitative screening (Qual Screen, n = 1,142,519), and quantitative screening (Quan Screen, n = 550,331) cohorts, and for Screened and Unscreened subgroups within screening cohorts. RESULTS: IRs (per 100,000) for infants aged 6 to 11 months were 1.12 in Control, 5.69 in Qual Screen (P <.0001), and 17.81 in Quan Screen (P <.0001); IRs for children aged 12 to 59 months were 7.29 in Control, 5.86 in Qual Screen (P =.28), and 6.36 in Quan Screen (P =.60). IRs for children aged 12 to 59 months in Unscreened or Screened subgroups remained at the same level. When patients diagnosed at younger than 6 months of age were excluded, the MR (per 100,000) under 60 months for Control was 4.21; those in Unscreened and Screened subgroups were 3.84 and 2.53 in Qual Screen (P =.30), and 3.20 and 1.97 in Quan Screen (P =.73), respectively; MRs between Control and Unscreened subgroups revealed no significant differences (P =.89 in Qual Screen, P =.85 in Quan Screen). CONCLUSION: Six-month screening resulted in a marked increase in incidence for infants with no significant decrease in incidence for children older than 1 year of age. A decrease in mortality was observed, but it was not significant. The usefulness of screening is questionable, because the decrease of mortality should be balanced against the adverse effect of overdiagnosis and the psychological burden on parents and children.

Age Factors↗