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Hiroshi Miwa,
Masato Shikami,
Mineaki Goto,
Shohei Mizuno,
Miyuki Takahashi,
Norikazu Tsunekawa-Imai,
Takamasa Ishikawa,
Motonori Mizutani,
Tomohiro Horio,
Mayuko Gotou,
Hidesuke Yamamoto,
Motohiro Wakabayashi,
Masaya Watarai,
Ichiro Hanamura,
Akira Imamura,
Hidetsugu Mihara,
Masakazu Nitta
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ABSTRACT: The shift in energy metabolism from oxidative phosphorylation to glycolysis can serve as a target for the inhibition of cancer growth. Here, we examined the metabolic changes induced by 2-deoxyglucose (2-DG), a glycolysis inhibitor, in leukemia cells by metabolome analysis. NB4 cells mainly utilized glucose as an energy source by glycolysis and oxidative phosphorylation in mitochondria, since metabolites in the glycolytic pathway and in the tricarboxylic acid (TCA) cycle were significantly decreased by 2-DG. In THP-1 cells, metabolites in the TCA cycle were not decreased to the same extent by 2-DG as in NB4 cells, which indicates that THP-1 utilizes energy sources other than glucose. TCA cycle metabolites in THP-1 cells may be derived from acetyl-CoA by fatty acid β-oxidation, which was supported by abundant detection of carnitine and acetylcarnitine in THP-1 cells. 2-DG treatment increased the levels of pentose phosphate pathway (PPP) metabolites and augmented the generation of NADPH by glucose-6-phosphate dehydrogenase. An increase in NADPH and upregulation of glutathione synthetase expression resulted in the increase in the reduced form of glutathione by 2-DG in NB4 cells. We demonstrated that a combination of 2-DG and inhibition of PPP by dehydroepiandrosterone (DHEA) effectively suppressed the growth of NB4 cells. The replenishment of the TCA cycle by fatty acid oxidation by carnitine palmitoyltransferase in THP-1 cells, treated by 2-DG, might be regulated by AMPK, as the combination of 2-DG and inhibition of AMPK by compound C potently suppressed the growth of THP-1 cells. Although 2-DG has been effective in preclinical and clinical studies, this treatment has not been fully explored due to concerns related to potential toxicities such as brain toxicity at high doses. We demonstrated that a combination of 2-DG and DHEA or compound C at a relatively low concentration effectively inhibits the growth of NB4 and THP-1 cells, respectively. These observations may aid in the identification of appropriate combinations of metabolic inhibitors at low concentrations which do not cause toxicities.
Oncology Reports 02/2013; · 1.84 Impact Factor
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Mayuko Gotou,
Ichiro Hanamura,
Hisao Nagoshi,
Motohiro Wakabayashi,
Natsumi Sakamoto,
Norikazu Tsunekawa,
Tomohiro Horio,
Mineaki Goto,
Shohei Mizuno,
Miyuki Takahashi, [......],
Hidesuke Yamamoto,
Akihito Hiramatsu,
Masaya Watarai,
Masato Shikami,
Akira Imamura,
Hidetsugu Mihara,
Tomohiko Taki, Hiroshi Miwa,
Masafumi Taniwaki,
Masakazu Nitta
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[hide abstract]
ABSTRACT: In this study, we established and analyzed a novel human myeloid leukemia cell line, AMU-AML1, from a patient with acute myeloid leukemia with multilineage dysplasia before the initiation of chemotherapy. AMU-AML1 cells were positive for CD13, CD33, CD117, and HLA-DR by flow cytometry analysis and showed a single chromosomal abnormality, 46, XY, t(12;22)(p13;q11.2), by G-banding and spectral karyotyping. Fluorescent in situ hybridization analysis indicated that the chromosomal breakpoint in band 12p13 was in the sequence from the 5' untranslated region to intron 1 of TEL and that the chromosomal breakpoint in band 22q11 was in the 3' untranslated region of MN1. The chimeric transcript and protein of MN1-TEL could not be detected by reverse-transcriptase polymerase chain reaction or Western blot analysis. However, the MN1 gene was amplified to three copies detected by array comparative genomic hybridization analysis, and the expression levels of the MN1 transcript and protein were high in AMU-AML1 cells when compared with other cell lines with t(12;22)(p13;q11-12). Our data showed that AMU-AML1 cells contain t(12;22)(p13;q11.2) without chimeric fusion of MN1 and TEL. The AMU-AML1 cells gained MN1 copies and had high expression levels of MN1. Thus, the AMU-AML1 cell line is useful for studying the biological consequences of t(12;22)(p13;q11.2) lacking chimeric MN1-TEL.
Genes Chromosomes and Cancer 10/2011; 51(1):42-53. · 3.31 Impact Factor
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Mayuko Gotou,
Ichiro Hanamura,
Hisao Nagoshi,
Motohiro Wakabayashi,
Natsumi Sakamoto,
Norikazu Tsunekawa,
Tomohiro Horio,
Mineaki Goto,
Shohei Mizuno,
Miyuki Takahashi, [......],
Hidesuke Yamamoto,
Akihito Hiramatsu,
Masaya Watarai,
Masato Shikami,
Akira Imamura,
Hidetsugu Mihara,
Tomohiko Taki, Hiroshi Miwa,
Masafumi Taniwaki,
Masakazu Nitta
[show abstract]
[hide abstract]
ABSTRACT: In this study, we established and analyzed a novel human myeloid leukemia cell line, AMU-AML1, from a patient with acute myeloid leukemia with multilineage dysplasia before the initiation of chemotherapy. AMU-AML1 cells were positive for CD13, CD33, CD117, and HLA-DR by flow cytometry analysis and showed a single chromosomal abnormality, 46, XY, t(12;22)(p13;q11.2), by G-banding and spectral karyotyping. Fluorescent in situ hybridization analysis indicated that the chromosomal breakpoint in band 12p13 was in the sequence from the 5′ untranslated region to intron 1 of TEL and that the chromosomal breakpoint in band 22q11 was in the 3′ untranslated region of MN1. The chimeric transcript and protein of MN1-TEL could not be detected by reverse-transcriptase polymerase chain reaction or Western blot analysis. However, the MN1 gene was amplified to three copies detected by array comparative genomic hybridization analysis, and the expression levels of the MN1 transcript and protein were high in AMU-AML1 cells when compared with other cell lines with t(12;22)(p13;q11-12). Our data showed that AMU-AML1 cells contain t(12;22)(p13;q11.2) without chimeric fusion of MN1 and TEL. The AMU-AML1 cells gained MN1 copies and had high expression levels of MN1. Thus, the AMU-AML1 cell line is useful for studying the biological consequences of t(12;22)(p13;q11.2) lacking chimeric MN1-TEL. © 2011 Wiley Periodicals, Inc.
Genes Chromosomes and Cancer 10/2011; 51(1):42 - 53. · 3.31 Impact Factor
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Kazuto Suganuma, Hiroshi Miwa,
Norikazu Imai,
Masato Shikami,
Mayuko Gotou,
Mineaki Goto,
Shohei Mizuno,
Miyuki Takahashi,
Hidesuke Yamamoto,
Akihito Hiramatsu,
Motohiro Wakabayashi,
Masaya Watarai,
Ichiro Hanamura,
Akira Imamura,
Hidetsugu Mihara,
Masakazu Nitta
[show abstract]
[hide abstract]
ABSTRACT: For generation of energy, cancer cells utilize glycolysis more vigorously than oxidative phosphorylation in mitochondria (Warburg effect). We examined the energy metabolism of four leukemia cell lines by using glycolysis inhibitor, 2-deoxy-d-glucose (2-DG) and inhibitor of oxidative phosphorylation, oligomycin. NB4 was relatively sensitive to 2-DG (IC(50): 5.75 mM), consumed more glucose and produced more lactate (waste product of glycolysis) than the three other cell lines. Consequently, NB4 was considered as a "glycolytic" leukemia cell line. Dependency on glycolysis in NB4 was confirmed by the fact that glucose (+) FCS (-) medium showed more growth and survival than glucose (-) FCS (+) medium. Alternatively, THP-1, most resistant to 2-DG (IC(50): 16.14 mM), was most sensitive to oligomycin. Thus, THP-1 was recognized to be dependent on oxidative phosphorylation. In THP-1, glucose (-) FCS (+) medium showed more growth and survival than glucose (+) FCS (-) medium. The dependency of THP-1 on FCS was explained, at least partly, by fatty acid oxidation because inhibitor of fatty acid β-oxidation, etomoxir, augmented the growth suppression of THP-1 by 2-DG. We also examined the mechanisms by which THP-1 was resistant to, and NB4 was sensitive to 2-DG treatment. In THP-1, AMP kinase (AMPK), which is activated when ATP becomes limiting, was rapidly phosphorylated by 2-DG, and expression of Bcl-2 was augmented, which might result in resistance to 2-DG. On the other hand, AMPK phosphorylation and augmentation of Bcl-2 expression by 2-DG were not observed in NB4, which is 2-DG sensitive. These results will facilitate the future leukemia therapy targeting metabolic pathways.
Leukemia & lymphoma 11/2010; 51(11):2112-9. · 2.40 Impact Factor
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Kazuyuki Shimada,
Takuhei Murase,
Kosei Matsue,
Masataka Okamoto,
Naoaki Ichikawa,
Norifumi Tsukamoto,
Nozomi Niitsu, Hiroshi Miwa,
Hideki Asaoku,
Hiroshi Kosugi,
Ako Kikuchi,
Morio Matsumoto,
Yoshio Saburi,
Yasufumi Masaki,
Kazuhito Yamamoto,
Motoko Yamaguchi,
Shigeo Nakamura,
Tomoki Naoe,
Tomohiro Kinoshita
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ABSTRACT: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity with a high incidence of central nervous system (CNS) involvement at diagnosis. To evaluate CNS involvement, particularly recurrence including progression on therapy and relapse of IVLBCL, we retrospectively analyzed 109 patients with IVLBCL receiving chemotherapies with or without rituximab. In 82 patients (75%) without CNS involvement at initial diagnosis, risk of CNS recurrence at 3 years was 25% with a median follow-up in survivors of 39 months (range, 2-158 months). In 27 patients (25%) with CNS involvement at initial diagnosis, risk of CNS recurrence at 1 year was 25% with a median follow-up in survivors of 18 months (range, 10-77 months). Duration from diagnosis to CNS recurrence tended to be short in patients with CNS involvement at diagnosis. No significant difference in risk of CNS recurrence was found between patients receiving chemotherapies with or without rituximab. On multivariate analysis skin involvement at initial diagnosis was identified as a predictive factor for CNS recurrence in patients without CNS involvement at diagnosis (hazard ratio, 5.27; 95% confidence interval, 1.59-17.4; P = 0.007). Survival rate after CNS recurrence at 2 years was 12% in patients without CNS involvement at diagnosis. Central nervous system recurrence is a serious complication in IVLBCL patients and optimal strategies for CNS involvement should be established to obtain further improvements to clinical outcomes in the rituximab era.
Cancer Science 06/2010; 101(6):1480-6. · 3.33 Impact Factor
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Norikazu Imai, Hiroshi Miwa,
Masato Shikami,
Kazuto Suganuma,
Mayuko Gotoh,
Akihito Hiramatsu,
Motohiro Wakabayashi,
Masaya Watarai,
Ichiro Hanamura,
Akira Imamura,
Hidetsugu Mihara,
Kenya Shitara,
Masabumi Shibuya,
Masakazu Nitta
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ABSTRACT: By using neutralizing monoclonal antibodies to vascular endothelial growth factor receptor type 1 (VEGFR1) and VEGFR2, we have shown that acute myelogenous leukemia (AML) cells with specific chromosome abnormalities are dependent on VEGF/VEGFR system. AML with t(8;21) is the most dependent subtype on VEGF with both VEGFR1 and VEGFR2. t(15;17)AML cells depend on VEGF with VEGFR1. AML cells with 11q23 abnormalities showed variable dependence on VEGF. The growth of t(11;19)AML cells are most extensively inhibited by anti-VEGFR1 antibody. Then, the growth of Kasumi-1, a t(8;21) cell line was suppressed by either anti-VEGFR1 antibody (p=0.0022) or anti-VEGFR2 antibody (p=0.0029) in a dose-dependent manner. The growth of NB4, a t(15;17) cell line was more potently suppressed by anti-VEGFR1 antibody (p=0.0111) than by anti-VEGFR2 antibody (p=0.0477). These results are quite concordant with the results of clinical samples with t(8;21) or t(15;17). In addition, anti-VEGFR2 monoclonal antibody significantly potentiated the growth inhibitory effect of idarubicin for Kasumi-1. As for downstream signals, we have shown that VEGFR2 transduce growth and survival signals through phosphorylation of Akt and MEK in leukemia cells (Kasumi-1). However, VEGFR1 transduce growth and survival signals through pathways other than MEK and Akt (NB4), although Akt phosphorylation may account for some of the VEGFR1 signals (Kasumi-1). Finally, our data suggested that autocrine pathway of VEGF and VEGFRs observed in AML cells with specific chromosomal translocations have contributed to leukemogenesis as activated signaling of receptor tyrosine kinase.
Leukemia research 04/2009; 33(12):1650-7. · 2.36 Impact Factor
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Kazuyuki Shimada,
Kosei Matsue,
Kazuhito Yamamoto,
Takuhei Murase,
Naoaki Ichikawa,
Masataka Okamoto,
Nozomi Niitsu,
Hiroshi Kosugi,
Norifumi Tsukamoto, Hiroshi Miwa,
Hideki Asaoku,
Ako Kikuchi,
Morio Matsumoto,
Yoshio Saburi,
Yasufumi Masaki,
Motoko Yamaguchi,
Shigeo Nakamura,
Tomoki Naoe,
Tomohiro Kinoshita
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ABSTRACT: To evaluate the safety and efficacy of rituximab-containing chemotherapies for intravascular large B-cell lymphoma (IVLBCL).
We retrospectively analyzed 106 patients (59 men, 47 women) with IVLBCL who received chemotherapy either with rituximab (R-chemotherapy, n = 49) or without rituximab (chemotherapy, n = 57) between 1994 and 2007 in Japan. The median patient age was 67 years (range, 34 to 84 years). The International Prognostic Index was high-intermediate/high in 97% of patients.
The complete response rate was higher for patients in the R-chemotherapy group (82%) than for those in the chemotherapy group (51%; P = .001). The median duration of follow-up for surviving patients was 18 months (range, 1 to 95 months). Progression-free survival (PFS) and overall survival (OS) rates at 2 years after diagnosis were significantly higher for patients in the R-chemotherapy group (PFS, 56%; OS, 66%) than for patients in the chemotherapy group (PFS, 27% with P = .001; OS, 46% with P = 0.01). Multivariate analysis revealed that the use of rituximab was favorably associated with PFS (hazard ratio [HR], 0.45; 95% CI, 0.25 to 0.80; P = .006) and OS (HR, 0.42; 95% CI, 0.21 to 0.85; P = .016). Treatment-related death was observed in three patients (6%) who received R-chemotherapy and in five patients (9%) who received chemotherapy.
Our data suggest improved clinical outcomes for patients with IVLBCL in the rituximab era. Future prospective studies of rituximab-containing chemotherapies are warranted.
Journal of Clinical Oncology 08/2008; 26(19):3189-95. · 18.37 Impact Factor
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ABSTRACT: Summary Eosinophilia sometimes occurs in acute myeloid leukaemia (AML) and several laboratories have reported that cells with the t(8;21) or structural abnormalities of chromosome 16 can proliferate and differentiate to eosinophils in the presence of IL-5 in vitro. However, cases without these chromosomal abnormalities can also have eosinophilia. We investigated the association between the expression of IL-5 receptor (IL-5R) gene, karyotype and phenotype in 35 patients with AML. All cases expressed the IL-3R but the IL-5R gene was expressed predominantly in leukaemic cells with either t(8;21) or CD4-positive immunophenotype and was associated with the presence of eosinophilia.
British Journal of Haematology 03/2008; 91(1):169 - 172. · 4.94 Impact Factor
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Norikazu Imai,
Masato Shikami, Hiroshi Miwa,
Kazuto Suganuma,
Akihito Hiramatsu,
Masaya Watarai,
Atsushi Satoh,
Masato Itoh,
Akira Imamura,
Hidetsugu Mihara,
Masakazu Nitta
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ABSTRACT: Several anti-angiogenic drugs have recently been clinically tested for haematological malignancies. To improve the efficacy of molecular target therapy against angiogenic molecules in acute myeloid leukaemia (AML), we examined the dependency of AML cells on the vascular endothelial growth factor (VEGF)/VEGF receptor type2 (VEGFR2) system by using VEGFR2 kinase inhibitor. Nineteen patient AML samples were cultured with or without VEGFR2 kinase inhibitor. All four t(8;21) viable AML cells showed significant reductions when treated with VEGFR2 kinase inhibitor, although VEGFR2 kinase inhibitor did not affect the cell proliferation of five t(15;17) AML samples. Other AML cases showed variable responses. VEGFR2 kinase inhibitor greatly suppressed the growth of Kasumi-1, a t(8;21) cell line in a dose-dependent manner through induction of apoptosis, but did not show any significant influence on NB4, a t(15;17) cell line. In addition, VEGFR2 kinase inhibitor potentiated the growth inhibitory effect of cytarabine in Kasumi-1. Finally, it was shown that the Akt phosphorylation was augmented by VEGF(165) in Kasumi-1, which was abrogated by VEGFR2 kinase inhibitor. NB4 showed undetectable Akt phosphorylation even with VEGF(165). These data demonstrated that t(8;21) AML cells are dependent on VEGF through VEGFR2, resulting in the phosphorylation of Akt.
British Journal of Haematology 01/2007; 135(5):673-82. · 4.94 Impact Factor
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ABSTRACT: In this study, the mRNA expression of p14(ARF) in t(8;21)AML cells was found to be significantly lower than acute myelocytic leukemia (AML) cells without t(8;21) chromosome abnormality, which was concordant with previous observation by Linggi et al. that AML1-MTG8 represses the transcription of p14(ARF). Although p53 mRNA expression level of t(8;21)AML cells was not low, p53 protein expression was reduced in t(8;21)AML cells. Genotoxic damage by ionizing radiation did not induce p53 upregulation in t(8;21)AML cells. Since p14(ARF) has been demonstrated to inhibit p53 degradation by binding to MDM2, repression of p14(ARF) expression in t(8;21)AML may facilitate the degradation of p53 by MDM2. Low p14(ARF) in t(8;21)AML may also account for the absence of upregulation of p53 by ionizing radiation. Then, we have shown that p53 expression level was inversely correlated with S/G2/M population of cell cycle in AML cells. Most of the t(8;21)AML are considered to be in p53(low) S/G2/M(high). It is now widely known that formation of AML1-MTG8 by t(8;21) translocation is a very early event in leukemogenesis, and AML1-MTG8 alone might have limited proliferative potential. Then, secondary oncogenic events such as activated receptor tyrosine kinase (like c-kit mutation), is necessary to become full-blown leukemia. Low p53 protein expression and insufficient induction of p53 by genotoxic damage might increase the opportunity to obtain additional oncogenic events, since genome guard function of p53 does not work in t(8;21)AML cells.
Leukemia Research 05/2006; 30(4):379-83. · 2.92 Impact Factor
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Nihon Naika Gakkai Zasshi 01/2006; 94(12):2606-8.
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Toshiko Ikai, Hiroshi Miwa,
Masato Shikami,
Akihito Hiramatsu,
Emi Tajima,
Hidesuke Yamamoto,
Norikazu Imai,
Akiko Hattori,
Kazuhiro Nishii,
Kazuhisa Miura,
Atsushi Satoh,
Masato Itoh,
Akira Imamura,
Hidetsugu Mihara,
Yoshiro Katoh,
Masakazu Nitta
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ABSTRACT: Vascular endothelial growth factor (VEGF) and its associated molecule, placenta growth factor (PlGF) are now known to support normal hematopoiesis, and leukemia cell growth. In this study, expression of VEGF and PlGF in acute lymphoblastic leukemia (ALL) cells was examined by real time reverse transcription-polymerase chain reaction in 20 patient samples. Expression of PlGF was more intense in Philadelphia chromosome positive (Ph(+)) ALL than in Ph(-) ALL cases. On the other hand, expression level of VEGF was not different between Ph(+) and Ph(-) cases. Then, PlGF was added to the two ALL cell lines, CRL1929 (Ph(+)), and Nalm6 (Ph(-)). The PlGF stimulated the growth of CRL1929 in time- and dose-dependent manners, although the growth of Nalm6 was not affected by PlGF. The growth stimulation of CRL1929 by PlGF was confirmed by the increase of S phase cells. And the growth promoting effect of PlGF on CRL1929 was cancelled by simultaneous addition of VEGFR1/Fc (which binds to PlGF and abrogates its function), but was not cancelled by VEGFR2/Fc (which does not bind to PlGF). Then, addition of VEGFR1/Fc to the simple culture of CRL1929 demonstrated growth inhibitory effect. These observations demonstrated that PlGF stimulates the growth of Ph(+) ALL cells by both autocrine and paracrine pathways. Finally, PlGF-VEGFR1 loop might be a therapeutic target to improve the prognosis of Ph(+) ALL.
European Journal Of Haematology 11/2005; 75(4):273-9. · 2.61 Impact Factor
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ABSTRACT: We report an unusual case of angioimmunoblastic T cell lymphoma arising in the setting of 5 years of immunosuppressive treatment for progressive systemic sclerosis. The lymph node lesion was accompanied by large blastic B cells with an association of Epstein-Barr virus. Southern blot study demonstrated the clonal rearrangement of T cell receptor beta-chain gene, but not of immunoglobulin heavy chain gene. Phenotypical examination of the lymph node also revealed the predominance of CD4+ T cells in addition to the proliferation of follicular dendritic cells, but no light chain restriction in large B cell components. In the clinical and laboratory aspects, neutrophilia (15.8 x 10(9)/l) and plasmacytosis (40%) in bone marrow were noted, which were considered to be closely related to elevated serum granulocyte colony-stimulating factor, interleukin (IL)-4 and IL-6. Based on the combined data described here, our preferred diagnosis was angioimmunoblastic T cell lymphoma with Epstein-Barr virus-associated B cell lymphoproliferative disorder, the pathogenesis of which was suggested to be closely associated with immunosuppressive treatment for progressive systemic sclerosis.
Acta Haematologica 02/2005; 114(2):108-12. · 1.35 Impact Factor
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Motohiro Wakabayashi, Hiroshi Miwa,
Masato Shikami,
Akihito Hiramatsu,
Toshiko Ikai,
Emi Tajima,
Hidesuke Yamamoto,
Kazuhisa Miura,
Atsushi Satoh,
Masato Itoh,
Akira Imamura,
Hidetsugu Mihara,
Yoshiro Katoh,
Masakazu Nitta
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ABSTRACT: Hematopoietic cells and endothelial cells are mutually correlated in their development and growth. Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietins (Angs), are thought to be associated with leukemia cell growth. In this study, we examined if the Angs-Tie2 autocrine pathway works in primary AML cells or not by using soluble Tie2-Fc, which inhibits Angs from binding to Tie2 receptor. After 48 h of culture with Tie2-Fc, nine AML cells from 19 examined samples were not influenced by Tie2-Fc (group A), while AML cells from remaining 10 patients demonstrated remarkable reduction of cell number by Tie2-Fc treatment (group B). Tie2 receptor, upon binding to Angs, are known to activate phosphatidyl-inositol 3 kinase (PI3 kinase). Then, we examined the effect of LY294002, a potent PI3 kinase inhibitor, on primary AML cells. Cell number reduction effect by the treatment of LY294002 was much more prominent in cells of group B than of group A. In addition, extent of cell number reduction by Tie2-Fc and LY294002 was quite well correlated. These observations demonstrated that cells from a part of AML were dependent on autocrine Angs-Tie2 pathway. This notion was further supported by the study of two AML cell lines, KG-1 and HL-60: the growth of KG-1 was suppressed by Tie2-Fc, and also by anti-Tie2 antibody, which inhibits receptor-ligand interaction, while that of HL-60 was not suppressed by Tie2-Fc or anti-Tie2 antibody. Our results will help to explore the angiogenesis-oriented or endothelial cell-mediated therapy for leukemia.
The Hematology Journal 02/2004; 5(4):353-60. · 1.86 Impact Factor
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Atsushi Satoh,
Toshiko Ikai, Hiroshi Miwa,
Norikazu Imai,
Akihito Hiramatsu,
Emi Tajima,
Hidesuke Yamamoto,
Motohiro Wakabayashi,
Kazuhisa Miura,
Masato Ito,
Masato Shikami,
Akira Imamura,
Hidetsugu Mihara,
Yoshiro Kato,
Masakazu Nitta
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ABSTRACT: We report a case of acute promyelocytic leukemia (APL) with drug-induced hypersensitivity syndrome associated with Epstein-Barr virus (EBV) infection. A 33-year-old woman was admitted because of APL. After complete remission was obtained with the use of all-trans retinoic acid (ATRA), intensive chemotherapy was administered. She developed high grade fever and severe systemic erythematous eruptions followed by cervical lymphoadenopathy, hepatosplenomegaly, hepatitis and hypotension in a state of myelosuppression during consolidation chemotherapy. Systemic corticosteroids alleviated the symptoms. Since an anti-EB VCA IgM antibody titer was continuously positive, persistent infection of EBV was suspected. In this case, EBV infection may have contributed to the development of drug-induced hypersensitivity syndrome.
Internal Medicine 02/2004; 43(1):74-8. · 0.94 Impact Factor
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ABSTRACT: We describe a patient who presented with aplastic anaemia associated with the Philadelphia (Ph1) chromosome during immunosuppressive therapy and who subsequently developed myelodysplastic syndrome (MDS) with monosomy 7. Initially the patient had hypocellular fatty marrow without leukaemic blasts or dysplastic features. Chromosome analysis showed 46, XY, t(9;22)(q34;q11) during immunosuppressive therapy, but no leukaemic transformation was detected. The patient showed gradual haematologic improvement and became transfusion independent. Thereafter, bone marrow dysplasia with monosomy 7 progressed following transfusion independence. These findings indicate that multiple cytogenetic evolutions occur in aplastic anaemia during immunosuppressive therapy, and that Ph1 chromosome may play a role in bone marrow suppression rather than development of leukaemia.
European Journal Of Haematology 09/2003; 71(2):130-2. · 2.61 Impact Factor
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ABSTRACT: We describe a patient who presented with aplastic anaemia associated with the Philadelphia (Ph1) chromosome during immunosuppressive therapy and who subsequently developed myelodysplastic syndrome (MDS) with monosomy 7. Initially the patient had hypocellular fatty marrow without leukaemic blasts or dysplastic features. Chromosome analysis showed 46, XY, t(9;22)(q34;q11) during immunosuppressive therapy, but no leukaemic transformation was detected. The patient showed gradual haematologic improvement and became transfusion independent. Thereafter, bone marrow dysplasia with monosomy 7 progressed following transfusion independence. These findings indicate that multiple cytogenetic evolutions occur in aplastic anaemia during immunosuppressive therapy, and that Ph1 chromosome may play a role in bone marrow suppression rather than development of leukaemia.
European Journal Of Haematology 07/2003; 71(2):130 - 132. · 2.61 Impact Factor
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ABSTRACT: Therapy-related myelodysplastic syndrome and therapy-related acute myelocytic leukemia (AML) are now recognized as hematologic malignancies that occur a few years after chemotherapy for primary malignancy with alkylating agents or topoisomerase II inhibitors. The secondary leukemia is usually AML and sometimes is preceded by a myelodysplastic syndrome. Acute lymphoblastic leukemia (ALL) as a secondary leukemia is quite rare, and secondary T-cell ALL after AML is even rarer. We report a case of a 56-year-old woman who developed T-cell ALL after a 3-year remission of AML (M2). We thought that this case would be extremely valuable for studying the etiology and biological characteristics of T-cell ALL as a secondary leukemia after AML.
International Journal of Hematology 07/2003; 77(5):518-21. · 1.27 Impact Factor
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Kazuhisa Miura,
Shinsuke Iida,
Ichiro Hanamura,
Miyuki Kato,
Shogo Banno,
Takashi Ishida,
Shigeru Kusumoto,
Genji Takeuchi, Hiroshi Miwa,
Masakazu Nitta,
Hiroshi Inagaki,
Tadaaki Eimoto,
Kenichi Nomura,
Masafumi Taniwaki,
Ryuzo Ueda
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ABSTRACT: Chromosomal translocations involving the immunoglobulin heavy chain gene (IgH) and nonrandom protooncogene loci are the hallmark of genetic alterations found not only in multiple myeloma (MM), but also in premalignant stages of MM, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). We studied the frequency of IgH (14q32) rearrangements and their partner chromosomes in 16 Japanese patients with MGUS (13 cases), and SMM (3 cases) by means of interphase double-color fluorescence in situ hybridization (DCFISH) applied to purified plasma cells and using CD138-bead selection. IgH rearrangement was recognized in nine of the patients (56.3%). Protooncogene loci juxtaposed to IgH were identified in seven cases including CCND1 (11q13) in six cases and FGFR3 (4p16) in one. Four out of the six t(11;14)-positive cases showed nuclear staining of the cyclin D1 protein, whereas none of the seven t(11;14)-negative cases did. Moreover, neither MUM1(6p25)-IgH nor MAFB(20q11)-IgH fusion signals were observed. This suggests to us that cyclin D1 deregulation due to the presence of t(11;14) is involved in the early development of plasma cell neoplasms, and that this event alone is not enough for the development of symptomatic myeloma.
Cancer Science 05/2003; 94(4):350-4. · 3.33 Impact Factor
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Hiroshi Miwa,
Eiichi Nagura,
Kazuyuki Shimizu,
Masakazu Nitta,
Atsushi Ichikawa,
Toshihito Ohno,
Tomohiro Kinoshita,
Toshihiko Shibata,
Hiroshi Sao,
Takuhei Murase,
Hideo Takeyama,
Atsushi Wakita,
Hidehiko Saito
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ABSTRACT: A new intensive chemotherapy regimen, DAD, composed of doxorubicin, melphalan and dexamethasone, was given to 17 patients with multiple myeloma. The end point of this regimen was to obtain a deep posttreatment nadir in the M-protein levels so as to increase the chance of plateau attainment which would be associated with prolonged survival in each patient. It was noteworthy that all the 17 evaluable patients achieved a partial response. Nine of the 17 (52.9%) attained a plateau. Ten of the 17 patients (58.8%) obtained a deep posttreatment nadir in their M-protein levels (IgG < 2,000 mg/dl, IgA < 1,000 mg/dl, BJP = 0 g/dl/day), and six of them reached a plateau phase, which was not significantly more frequent than those who did not obtain a deep posttreatment nadir in their M-protein levels (three of seven reached plateau phase). The median survival of the 17 patients (37.6 months) was significantly prolonged compared with that of patients treated with our previous chemotherapy regimens, VMCP (22.5 months) and MMPP (23.5 months), and was comparable to that of MMCP (29.5 months).
[Rinshō ketsueki] The Japanese journal of clinical hematology 11/2002; 43(11):982-7.
