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Biomedical subjects

Hitoshi Kiyoi

Publications and source records attributed to Hitoshi Kiyoi.

At least 19 recordsLinked to original sources
PubMed2006

Clinical features and outcome of T-lineage acute lymphoblastic leukemia in adults: a low initial white blood cell count, as well as a high count predict decreased survival rates.

Although biological and clinical features differ between B-lineage acute lymphoblastic leukemia (ALL) and T-lineage ALL (T-ALL), there have been few reports that focused on the prognosis for T-ALL in adults, primarily due to its rarity. Here, we studied the long-term outcomes and prognostic factors specific for adult T-ALL by combining patient data from the three prospective trials conducted by the Japan Adult Leukemia Study Group (JALSG). Among 559 patients whose immunophenotypes could be evaluated, 87 (15.6%) were identified as T-ALL. Of them, 66 patients (75.8%) achieved complete remission, and relapse occurred in 41 patients. With a median follow-up for surviving patients of 7.5 years, the probability of overall survival was 35.0% at 5 years. Risk factor analysis revealed that serum albumin levels, initial white blood cell (WBC) counts, and age had independent values for predicting survival. For WBC, not only the high-count group (50 x 10(9)l(-1) or higher), but also the low-count group (less than 3 x 10(9)l(-1)) showed a significantly lower survival rates than the intermediate-count group (p=0.0055 and 0.0037, respectively). Although our findings need confirmation, these results will be helpful in the identification of prognostically distinct subgroups within adult T-ALL.

Adolescent↗
PubMed2006

Disseminated intravascular coagulation in acute leukemia: clinical and laboratory features at presentation.

BACKGROUND: Although there are two major scoring systems for the clinical diagnosis of disseminated intravascular coagulation (DIC), the validity of these systems for leukemia-associated DIC remains to be confirmed. METHODS: By analyzing 125 newly diagnosed acute leukemia patients, we investigated clinical and laboratory features of leukemia-associated DIC, and determined the validity of the two established criteria. RESULTS: A total of 36 patients (29%) were diagnosed with DIC according to expert opinion, a method regarded as the de facto gold standard. Leukemia-associated DIC is characterized by rare manifestation of organ failure because of thrombosis and no relevance of the platelet count for the diagnosis. The results of receiver operating characteristics analysis favored fibrin degradation product (FDP) rather than D-dimer as the fibrin-related marker test. Although prothrombin time, plasma fibrinogen, and serum FDP levels were significantly different for patients with and without DIC, multivariate analysis identified FDP levels to be the only factor associated with DIC diagnosis. The cut-off level of 15 microg/mL for FDP was found to be the most effective to differentiate DIC from non-DIC, resulting in diagnostic sensitivity and specificity of 92% and 96%, respectively. The diagnostic results for our patients produced with this FDP-based system were at least comparable with or superior to those obtained with the two currently available scoring systems. CONCLUSIONS: Our findings suggest that an FDP-based criterion may be applicable for the diagnosis of leukemia-associated DIC. Although it appears to be simple and practicable enough for clinical use, prospective validation of this criterion is needed.

Acute Disease↗
PubMed2006

Histone deacetylase 3 (HDAC3) is recruited to target promoters by PML-RARalpha as a component of the N-CoR co-repressor complex to repress transcription in vivo.

PML-RARalpha is a chimeric transcription factor tightly associated with acute promyelocytic leukemia. PML-RARalpha plays an important role in the aberrant transcription repression on the target genes of wild-type retinoic acid receptors. Here, we demonstrated that HDAC3, one component of the N-CoR transcription repressor complex, is a key regulator of the transcription repression by PML-RARalphain vivo. Using immunoprecipitation, we demonstrated that PML-RARalpha interacts with N-CoR/HDAC3 in vivo without ligand. Next, using chromatin immunoprecipitation (ChIP) assay, this N-CoR/HDAC3 co-repressor complex was recruited to the endogenous target promoters (RARbeta and CYP26) through PML-RARalpha. The neighboring histones were de-acetylated and gene expression was repressed. When HDAC3 protein was knocked down by RNA interference in PML-RARalpha-expressing cells, the endogenous target genes were significantly activated, which was also confirmed by promoter-luciferase reporter assay. These results provide evidence to show that the N-CoR/HDAC3 co-repressor complex is involved in the aberrant transcription regulation in PML-RARalpha-expressing cells.

Base Sequence↗
PubMed2006

Micafungin, a novel antifungal agent, as empirical therapy in acute leukemia patients with febrile neutropenia.

OBJECTIVE: Invasive fungal infection is a major cause of morbidity and mortality in patients with febrile neutropenia unresponsive to antibacterial treatment. Empirical antifungal therapy with amphotericin B has been the standard of care for these patients; however, there remains a need for less toxic alternative drugs. PATIENTS AND METHODS: We conducted a prospective study to evaluate the efficacy and safety of micafungin (MCFG), a novel antifungal agent of the echinocandin class, in an empirical therapy setting for patients with febrile neutropenia. RESULTS: A total of 31 patients with acute leukemia who developed febrile neutropenia were enrolled in the study. Among them, 18 patients fulfilling the protocol-defined criteria, including 10 with persistent fever and 8 with recurrent fever, received MCFG empirically. Underlying diseases consisted of acute myeloid leukemia (n=15) and acute lymphoblastic leukemia (n=3). The median duration of neutropenia and drug administration was 22 and 9.5 days, respectively. Treatment success, defined as defervescence during the neutropenic period, absence of breakthrough fungal infections, and requiring no replacement of antifungal drugs, was achieved in 14 patients (78%). None of the patients required discontinuation or dose reduction due to adverse events except for one patient with severe hypokalemia. CONCLUSIONS: Although the studied patients were limited in number, our results indicate that MCFG is an encouraging agent for empirical antifungal therapy in patients with febrile neutropenia, and deserves further investigation in large-scale studies.

Adolescent↗
PubMed2006

PTPN11, RAS and FLT3 mutations in childhood acute lymphoblastic leukemia.

PTPN11, the gene which encodes protein tyrosine phosphatase SHP-2, plays an important role in regulating intracellular signaling. Germline mutations in PTPN11 were first observed in Noonan syndrome, while somatic mutations were identified in hematological myeloid malignancies. Recently, PTPN11 mutations have been reported in children with acute lymphoblastic leukemia (ALL). In the present study, we investigated the prevalence of mutations in PTPN11, RAS and FLT3 in samples from 95 Japanese children with ALL. We observed exon 3 and 8 missense mutations of PTPN11 in 6 children with B precursor ALL. One patient with Down syndrome and ALL had PTPN11 mutation. We also identified RAS mutations in ten patients and FLT3 internal tandem duplication (FLT3/ITD) in one patient. None of the patients had simultaneous mutations in PTPN11 and RAS, while one patient had both PTPN11 and FLT3 mutations. These data suggest that PTPN11 mutation may play an important role for leukemogenesis in a proportion of children with ALL, particularly B precursor ALL.

Adolescent↗
PubMed2006

Genomewide array-based comparative genomic hybridization analysis of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is typically associated with the t(15;17) that generates the PML-RARA fusion protein. Animal models have shown that although the fusion protein is necessary, it is insufficient for the development of APL, implying that additional mechanisms are responsible for full-blown leukemia. The mutation of specific genes has been implicated in leukemogenesis; however, alterations in gene copy number have not been well investigated. Here, we applied the genomewide array-comparative genomic hybridization technique to 30 APL clinical samples and 2 APL cell lines. It was found that (1) approximately half the clinical samples (14 of 30 APL cases) had no detectable chromosomal imbalances; and (2) the remaining 16 cases, including the cell lines, exhibited recurrent chromosomal imbalances, such as loss of 1p36, 2p11, 16p, and 17p, and gain of 8p, 8q, and 13q. These results suggest that chromosomal imbalances are largely absent in APL, although some nonrandom chromosomal imbalances could be linked to the development of APL in a limited number of cases.

Adolescent↗
PubMed2006

Establishment of a myeloid leukemia cell line, TRL-01, with MLL-ENL fusion gene.

We established a leukemia cell line derived from therapy-related acute myeloid leukemia with the t(11;19) by xenotransplantation into the NOD/SCID mouse with IL-2Rgamma(c)-/- (NOG mouse). The cell line, TRL-01, could be serially transplanted from mouse to mouse and also grown in an adherence-dependent manner on a murine bone marrow stroma cell line, HESS-5. TRL-01 had the same immunophenotype as the original leukemia cells: positive for CD13, CD33, CD11a, CD18, CD29, CD49d, CD49e, CD54, CD62L, and CD117, and negative for CD3, CD4, CD8, CD19, CD34, CD41a, CD41b, CD135, and myeloperoxidase. Translocation (11;19)(q23;p13) in both the original sample and TRL-01 generated MLL-ENL chimeric transcripts joining exon 6 and exon 4, respectively, which has a novel isoform. In cultures of TRL-01, addition of GM-CSF, SCF, and G-CSF and adhesion to fibronectin-coated plates promoted transient proliferation and survival, although they did not support long-term culture. Subcutaneous injection caused a tumor to form only when HESS-5 was coinjected at the same site. These results suggest that TRL-01 is a useful cell line for studying not only the leukemia-related biology of MLL-ENL but also the intercellular association between leukemia and stroma.

Adult↗
PubMed2006

Nucleophosmin: a versatile molecule associated with hematological malignancies.

Nucleophosmin (NPM) is a nucleolar phosphoprotein that plays multiple roles in ribosome assembly and transport, cytoplasmic-nuclear trafficking, centrosome duplication and regulation of p53. In hematological malignancies, the NPM1 gene is frequently involved in chromosomal translocation, mutation and deletion. The NPM1 gene on 5q35 is translocated with the anaplastic lymphoma kinase (ALK) gene in anaplastic large cell lymphoma with t(2;5). The MLF1 and RARA genes are fused with NPM1 in myelodysplastic syndrome and acute myeloid leukemia (AML) with t(3;5) and acute promyelocytic leukemia with t(5;17), respectively. In each fused protein, the N-terminal NPM portion is associated with oligomerization of a partner protein leading to altered signal transduction or transcription. Recently, mutations of exon 12 have been found in a significant proportion of de novo AML, especially in those with a normal karyotype. Mutant NPM is localized aberrantly in the cytoplasm, but the molecular mechanisms for leukemia remain to be studied. Studies of knock-out mice have revealed new aspects regarding NPM1 as a tumor-suppressor gene. This review focuses on the clinical significance of the NPM1 gene in hematological malignancies and newly discovered roles of NPM associated with oncogenesis.

Animals↗
PubMed2006

FLT3 mutations in acute myeloid leukemia.

The prevalence of an internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence and a missense mutation of D835 within the kinase domain of the FLT3 gene is 15-35% and 5-10% of adults with acute myeloid leukemia (AML), respectively. In addition, point mutations, deletions, and insertions have been found in the juxtamembrane domain and in the other codons within the kinase domain, though these are less common. Several large-scale studies in well-documented patients published to date have demonstrated that FLT3 mutations are strongly associated with a poor prognosis and a high leukemia cell count in patients with AML, suggesting that FLT3 mutations are involved in disease progression. Because the detection of FLT3 mutations is fast, easy, and inexpensive, mutation analysis should be performed as a routine test. This chapter describes methods for detecting ITD and D835 mutations in the FLT3 gene.

Acute Disease↗
PubMed2006

Establishment of a stroma-dependent human acute myelomonocytic leukemia cell line, NAMO-2, with FLT3 tandem duplication.

We have established a stroma-dependent myelomonocytic cell line, NAMO-2, with FLT3 internal tandem duplication (FLT3/ITD). Leukemia cells from a patient with acute myelomonocytic leukemia were administered to form subcutaneous tumors in nude mice, which were maintained successively, although we failed to establish continuously growing cells from the original leukemia cell culture. In the cultures of cells from subcutaneous tumors, there were stroma cells that had originated from the nude mice and showed continuous growth. The leukemia cells showed continuous growth dependent on this stroma, and this cell line was named NAMO-2. Detection of FLT3/ITD by the reverse transcriptase polymerase chain reaction (PCR) and genomic PCR showed that NAMO-2 was homozygous for FLT3/ITD. Constitutive activation of FLT3 was detected by Western blotting, and the phosphorylation of Akt, MEK, and STAT5 was also observed. FLT3 kinase inhibitor AG1296 specifically inhibited cell growth. NAMO-2 provides a useful tool to analyze adherence-dependent survival signaling of leukemia with FLT3/ITD and a model for the screening of FLT3 kinase inhibitors.

Animals↗
PubMed2006

Biology, clinical relevance, and molecularly targeted therapy in acute leukemia with FLT3 mutation.

Overexpression and activating mutations of receptor tyrosine kinases (RTKs) are known to be involved in the pathophysiology of several kinds of cancer cells. FMS-like receptor tyrosine kinase 3 (FLT3), together with KIT, FMS, and platelet-derived growth factor receptor, is a class III RTK. FLT3 mutations were first reported as internal tandem duplication (FLT3/ITD) of the juxtamembrane domain-coding sequence; subsequently, a missense point mutation at the D835 residue and point mutations, deletions, and insertions in the codons surrounding D835 within a FLT3 tyrosine kinase domain (FLT3/KDMs) have been found. FLT3 mutations are the most frequent genetic alterations so far reported in acute myeloid leukemia and are involved in the signaling pathway of autonomous proliferation and differentiation block in leukemia cells. Several large-scale studies have confirmed that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis. Therefore, routine screening for FLT3 mutations is recommended to stratify patients into distinct risk groups. However, because high-dose chemotherapy and stem cell transplantation cannot overcome the adverse effects of FLT3 mutations, the development of FLT3 kinase inhibitors is expected to produce a more efficacious therapeutic strategy for leukemia therapy.

Acute Disease↗
PubMed2005

Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia.

Recently, somatic mutations of the nucleophosmin gene (NPM1), which alter the subcellular localization of the product, have been reported in acute myeloid leukemia (AML). We analyzed the clinical significance of NPM1 mutations in comparison with cytogenetics, FLT3, NRAS, and TP53 mutations, and a partial tandem duplication of the MLL gene (MLL-TD) in 257 patients with AML. We found NPM1 mutations, including 4 novel sequence variants, in 64 of 257 (24.9%) patients. NPM1 mutations were associated with normal karyotype and with internal tandem duplication (ITD) and D835 mutations in FLT3, but not with other mutations. In 190 patients without the M3 French-American-British (FAB) subtype who were treated with the protocol of the Japan Adult Leukemia Study Group, multivariate analyses showed that the NPM1 mutation was a favorable factor for achieving complete remission but was associated with a high relapse rate. Sequential analysis using 39 paired samples obtained at diagnosis and relapse showed that NPM1 mutations were lost at relapse in 2 of the 17 patients who had NPM1 mutations at diagnosis. These results suggest that the NPM1 mutation is not necessarily an early event during leukemogenesis or that leukemia clones with NPM1 mutations are sensitive to chemotherapy.

Adolescent↗
PubMed2005

Long-term outcomes for unselected patients with acute myeloid leukemia categorized according to the World Health Organization classification: a single-center experience.

The actual utility of a new classification system of acute myeloid leukemia (AML) recently introduced by the World Health Organization (WHO) has not been thoroughly investigated yet. In this study, we evaluated long-term outcomes of unselected AML patients categorized according to the new WHO classification. Between 1990 and 2002, 109 adult AML cases were referred to our hospital. For the entire population, the median survival duration was 1.2 yr with a 5-yr survival rate of 31%. AML with recurrent genetic abnormalities accounted for 26%, AML with multilineage dysplasia for 29%, therapy-related AML for 13%, and AML not otherwise categorized for 32% of classifiable cases. Among the four groups, a significant difference was observed in terms of overall survival (P < 0.0001). Univariate analysis showed that six variables affected survival: cytogenetic risk, age, multilineage dysplasia, prior chemo/radiotherapy, type of treatment (intensive or palliative), and transplantation. However, in multivariate analysis no adverse prognostic impact of multilineage dysplasia and prior chemo/radiotherapy was detected (P = 0.4979 and 0.8702), whereas cytogenetic risk and patient age maintained their prognostic value (P = 0.0005 and 0.0100). These results indicate that outcomes for AML patients appear to be distinguished on the basis of the WHO classification, but the prognostic significance of multilineage dysplasia and prior therapy is lost after adjusting for cytogenetic risk and age. Our findings suggest that the WHO classification may be strengthened by greater emphasis on genetic/cytogenetic information.

Adolescent↗
PubMed2005

BMI-1 is highly expressed in M0-subtype acute myeloid leukemia.

Recent studies have suggested that one of the polycomb group genes, BMI-1, has an important role in the maintenance of normal and leukemic stem cells by repressing the INK4a/ARF locus. Here, we quantitatively examined BMI-1 expression level in samples from patients with acute myeloid leukemia (AML) and other hematologic malignancies. Moderate to high BMI-1 expression was detected in AML patients, and the BMI-1 expression levels in AML samples were significantly higher than in normal bone marrow controls (P = .0011). Specimens of French-American-British classification subtype M0 showed higher relative expression of the BMI-1 transcript (median, 390.2 3 10(-3)) than the other subtypes (median, 139.0 3 10(-3)) (P < .0001). Leukemia other than AML showed low to moderate expression. INK4a-ARF transcript expression tended to be inverse proportion to that of BMI-1. In an M0 patient with a high BMI-1 transcript level, the INK4a-ARF transcript level fell promptly and maintained a low value after the patient achieved complete remission. These results indicated that a subgroup of M0 patients has a high expression level of polycomb group gene BMI-1, which may contribute to leukemogenesis.

Acute Disease↗
PubMed2005

Clinical significance of FLT3 in leukemia.

FLT3 is a class III receptor tyrosine kinase together with KIT, FMS and PDGFR. FLT3 mutations were first reported as internal tandem duplication (FLT3/ITD) of the juxtamembrane domain-coding sequence, and subsequently as a missense mutation of D835 (FLT3/KDM) within a kinase domain. Furthermore, point mutations, deletions, and insertions in the codons surrounding D835 have also been found. FLT3/ITD and FLT3/KDM occur in 15% to 35% and 5% to 10%, respectively, of patients with AML. FLT3 mutations are, therefore, the most frequent genetic alterations so far reported in AML. Several large-scale studies have confirmed that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis. Although the clinical significance of FLT3/KDM is controversial, the meta-analysis suggests its adverse effect on the outcome. FLT3/ITD is far less common in patients with ALL, whereas FLT3/KDM is recurrently found in patients with ALL, especially in those harboring an MLL gene rearrangement or hyperdiploidy. The overexpression of FLT3 transcripts has been demonstrated in a pro-portion of the AML patients without FLT3 mutations, which are associated with a poor prognosis for overall survival. Routine screening of FLT3 mutations is recommended to stratify the patients into distinct risk groups, while the optimal treatment strategy for patients with FLT3 mutations should be further evaluated.

Adult↗