10 results on '"Goi, K"'
Search Results
2. Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors.
- Author
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Zhang X, Inukai T, Hirose K, Akahane K, Kuroda I, Honna-Oshiro H, Kagami K, Goi K, Nakamura K, Kobayashi M, Endo M, Yagita H, Kurosawa H, Thomas Look A, Honda H, Inaba T, Nakazawa S, and Sugita K
- Subjects
- Blotting, Western, Cell Proliferation, DNA-Binding Proteins metabolism, Electrophoretic Mobility Shift Assay, Humans, Luciferases metabolism, Oncogene Proteins, Fusion metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Promoter Regions, Genetic genetics, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors metabolism, Transcriptional Activation, Tumor Cells, Cultured, Up-Regulation, Apoptosis drug effects, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 19 genetics, DNA-Binding Proteins genetics, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand genetics, TNF-Related Apoptosis-Inducing Ligand pharmacology, Transcription Factors genetics, Translocation, Genetic genetics
- Abstract
t(17;19)-acute lymphoblastic leukemia (ALL) shows extremely poor prognosis. E2A-HLF derived from t(17;19) blocks apoptosis induced by the intrinsic mitochondrial pathway and has a central role in leukemogenesis and chemoresistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed on cytotoxic T cells and natural killer cells and binds with death receptors (DR4/DR5), inducing apoptosis by dual activation of intrinsic and extrinsic pathways, and TRAIL mediates the graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT). We found that cell lines and patients' samples of t(17;19)-ALL expressed death receptors for TRAIL, and recombinant soluble TRAIL immediately induced apoptosis into t(17;19)-ALL cell lines. E2A-HLF induced gene expression of DR4/DR5, which was dependent on the DNA-binding and transactivation activities of E2A-HLF through the 5' upstream region of the start site at least in the DR4 gene. Introduction of E2A-HLF into non-t(17;19)-ALL cell line upregulated DR4 and DR5 expression, and sensitized to proapoptotic activity of recombinant soluble TRAIL. Finally, a newly diagnosed t(17;19)-ALL patient underwent allo-SCT immediately after induction of first complete remission, and the patient has survived without relapse for over 3-1/2 years after allo-SCT. These findings suggest that E2A-HLF sensitizes t(17;19)-ALL to the GVL effect by upregulating death receptors for TRAIL.
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- 2012
- Full Text
- View/download PDF
3. Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19).
- Author
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Hirose K, Inukai T, Kikuchi J, Furukawa Y, Ikawa T, Kawamoto H, Oram SH, Göttgens B, Kiyokawa N, Miyagawa Y, Okita H, Akahane K, Zhang X, Kuroda I, Honna H, Kagami K, Goi K, Kurosawa H, Look AT, Matsui H, Inaba T, and Sugita K
- Subjects
- Adaptor Proteins, Signal Transducing, Apoptosis physiology, Blotting, Western, Cell Line, Tumor, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 19, Fetal Blood cytology, Gene Expression Regulation, Leukemic, Humans, LIM Domain Proteins, Lentivirus genetics, Metalloproteins metabolism, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cells, B-Lymphoid cytology, Promoter Regions, Genetic physiology, Proto-Oncogene Proteins, RNA, Small Interfering, Transcription Factors genetics, Up-Regulation genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Metalloproteins genetics, Oncogene Proteins, Fusion metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cells, B-Lymphoid physiology, Transcription Factors metabolism, Translocation, Genetic
- Abstract
LMO2, a critical transcription regulator of hematopoiesis, is involved in human T-cell leukemia. The binding site of proline and acidic amino acid-rich protein (PAR) transcription factors in the promoter of the LMO2 gene plays a central role in hematopoietic-specific expression. E2A-HLF fusion derived from t(17;19) in B-precursor acute lymphoblastic leukemia (ALL) has the transactivation domain of E2A and the basic region/leucine zipper domain of HLF, which is a PAR transcription factor, raising the possibility that E2A-HLF aberrantly induces LMO2 expression. We here demonstrate that cell lines and a primary sample of t(17;19)-ALL expressed LMO2 at significantly higher levels than other B-precursor ALLs did. Transfection of E2A-HLF into a non-t(17;19) B-precursor ALL cell line induced LMO2 gene expression that was dependent on the DNA-binding and transactivation activities of E2A-HLF. The PAR site in the LMO2 gene promoter was critical for E2A-HLF-induced LMO2 expression. Gene silencing of LMO2 in a t(17;19)-ALL cell line by short hairpin RNA induced apoptotic cell death. These observations indicated that E2A-HLF promotes cell survival of t(17;19)-ALL cells by aberrantly up-regulating LMO2 expression. LMO2 could be a target for a new therapeutic modality for extremely chemo-resistant t(17;19)-ALL.
- Published
- 2010
- Full Text
- View/download PDF
4. Specific induction of CD33 expression by E2A-HLF: the first evidence for aberrant myeloid antigen expression in ALL by a fusion transcription factor.
- Author
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Akahane K, Inukai T, Inaba T, Kurosawa H, Look AT, Kiyokawa N, Fujimoto J, Goto H, Endo M, Zhang X, Hirose K, Kuroda I, Honna H, Kagami K, Goi K, Nakazawa S, and Sugita K
- Subjects
- Antigens, CD genetics, Antigens, Differentiation, Myelomonocytic genetics, Apoptosis, Blotting, Western, Cell Proliferation, Cells, Cultured, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 19 genetics, DNA-Binding Proteins genetics, Flow Cytometry, Humans, Oncogene Proteins, Fusion genetics, Phosphorylation, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cells, B-Lymphoid metabolism, Precursor Cells, B-Lymphoid pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Sialic Acid Binding Ig-like Lectin 3, Transcription Factors genetics, Translocation, Genetic genetics, Tyrosine metabolism, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, DNA-Binding Proteins metabolism, Oncogene Proteins, Fusion metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Transcription Factors metabolism
- Published
- 2010
- Full Text
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5. Genetic abnormalities involved in t(12;21) TEL-AML1 acute lymphoblastic leukemia: analysis by means of array-based comparative genomic hybridization.
- Author
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Tsuzuki S, Karnan S, Horibe K, Matsumoto K, Kato K, Inukai T, Goi K, Sugita K, Nakazawa S, Kasugai Y, Ueda R, and Seto M
- Subjects
- Adolescent, Cell Line, Tumor, Cell Proliferation, Child, Child, Preschool, Chromosome Deletion, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, In Situ Hybridization, Fluorescence, Male, Neoplasm Proteins genetics, Nucleic Acid Hybridization methods, Oligonucleotide Array Sequence Analysis, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 21, Core Binding Factor Alpha 2 Subunit genetics, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Translocation, Genetic
- Abstract
The TEL (ETV6)-AML1 (RUNX1) chimeric gene fusion is the most common genetic abnormality in childhood acute lymphoblastic leukemias. Evidence suggests that this chimeric gene fusion constitutes an initiating mutation that is necessary but insufficient for the development of leukemia. In a search for additional genetic events that could be linked to the development of leukemia, we applied a genome-wide array-comparative genomic hybridization technique to 24 TEL-AML1 leukemia samples and two cell lines. It was found that at least two chromosomal imbalances were involved in all samples. Recurrent regions of chromosomal imbalance (>10% of cases) and representative involved genes were gain of chromosomes 10 (17%) and 21q (25%; RUNX1) and loss of 12p13.2 (87%; TEL), 9p21.3 (29%; p16INK4a/ARF), 9p13.2 (25%; PAX5), 12q21.3 (25%; BTG1), 3p21 (21%; LIMD1), 6q21 (17%; AIM1 and BLIMP1), 4q31.23 (17%; NR3C2), 11q22-q23 (13%; ATM) and 19q13.11-q13.12 (13%; PDCD5). Enforced expression of TEL and to a lesser extent BTG1, both single genes known to be located in their respective minimum common region of loss, inhibited proliferation of the TEL-AML1 cell line Reh. Together, these findings suggest that some of the genes identified as lost by array-comparative genomic hybridization may partly account for the development of leukemia.
- Published
- 2007
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6. Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19.
- Author
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Inukai T, Hirose K, Inaba T, Kurosawa H, Hama A, Inada H, Chin M, Nagatoshi Y, Ohtsuka Y, Oda M, Goto H, Endo M, Morimoto A, Imaizumi M, Kawamura N, Miyajima Y, Ohtake M, Miyaji R, Saito M, Tawa A, Yanai F, Goi K, Nakazawa S, and Sugita K
- Subjects
- Adolescent, Calcium blood, Child, Child, Preschool, Female, Humans, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 19, DNA-Binding Proteins genetics, Hypercalcemia complications, Hypercalcemia genetics, Oncogene Proteins, Fusion genetics, Parathyroid Hormone-Related Protein genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Transcription Factors genetics, Translocation, Genetic
- Abstract
Hypercalcemia is relatively rare but clinically important complication in childhood leukemic patients. To clarify the clinical characteristics, mechanisms of hypercalcemia, response to management for hypercalcemia, incidence of t(17;19) and final outcome of childhood acute lymphoblastic leukemia (ALL) accompanied by hypercalcemia, clinical data of 22 cases of childhood ALL accompanied by hypercalcemia (>12 mg/dl) reported in Japan from 1990 to 2005 were retrospectively analyzed. Eleven patients were 10 years and older. Twenty patients had low white blood cell count (<20 x 10(9)/l), 15 showed hemoglobin> or =8 g/dl and 14 showed platelet count > or =100 x 10(9)/l. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcemia was confirmed in 11 of the 16 patients in whom elevated-serum level or positive immunohistochemistry of PTHrP was observed. Hypercalcemia and accompanying renal insufficiency resolved quickly, particularly in patients treated with bisphosphonate. t(17;19) or add(19)(p13) was detected in five patients among 17 patients in whom karyotypic data were available, and the presence of E2A-HLF was confirmed in these five patients. All five patients with t(17;19)-ALL relapsed very early. Excluding the t(17;19)-ALL patients, the final outcome of ALL accompanied by hypercalcemia was similar to that of all childhood ALL patients, indicating that the development of hypercalcemia itself is not a poor prognostic factor.
- Published
- 2007
- Full Text
- View/download PDF
7. Clonotypic analysis of acute lymphoblastic leukemia with a double TEL-AML1 fusion at onset and relapse.
- Author
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Inukai T, Yokota S, Okamoto T, Nemoto A, Akahane K, Takahashi K, Sato H, Goi K, Nakazawa S, and Sugita K
- Subjects
- Chromosome Aberrations, Clone Cells, Cytogenetic Analysis, Disease Progression, Female, Humans, In Situ Hybridization, Fluorescence, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Recurrence, Reverse Transcriptase Polymerase Chain Reaction, Core Binding Factor Alpha 2 Subunit genetics, Down Syndrome genetics, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Published
- 2006
- Full Text
- View/download PDF
8. The E2A-HLF oncoprotein activates Groucho-related genes and suppresses Runx1.
- Author
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Dang J, Inukai T, Kurosawa H, Goi K, Inaba T, Lenny NT, Downing JR, Stifani S, and Look AT
- Subjects
- Amino Acid Sequence, Animals, Apoptosis, Base Sequence, Basic-Leucine Zipper Transcription Factors, Cell Line, Cell Lineage, Co-Repressor Proteins, Core Binding Factor Alpha 2 Subunit, DNA, Complementary, Drosophila melanogaster, Humans, Leukemia, B-Cell, Mice, Molecular Sequence Data, Nuclear Proteins genetics, Nuclear Proteins metabolism, Oncogene Proteins, Fusion genetics, Proteins genetics, Trans-Activators genetics, Transcriptional Activation, Up-Regulation, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Leucine Zippers, Oncogene Proteins, Fusion metabolism, Proto-Oncogene Proteins, Repressor Proteins genetics, Repressor Proteins metabolism, Trans-Activators metabolism, Transcription Factors genetics
- Abstract
The E2A-HLF fusion gene, formed by the t(17;19)(q22;p13) chromosomal translocation in leukemic pro-B cells, encodes a chimeric transcription factor consisting of the transactivation domain of E2A linked to the bZIP DNA-binding and protein dimerization domain of hepatic leukemia factor (HLF). This oncoprotein blocks apoptosis induced by growth factor deprivation or irradiation, but the mechanism for this effect remains unclear. We therefore performed representational difference analysis (RDA) to identify downstream genetic targets of E2A-HLF, using a murine FL5.12 pro-B cell line that had been stably transfected with E2A-HLF cDNA under the control of a zinc-regulated metallothionein promoter. Two RDA clones, designated RDA1 and RDA3, were differentially upregulated in E2A-HLF-positive cells after zinc induction. The corresponding cDNAs encoded two WD40 repeat-containing proteins, Grg2 and Grg6. Both are related to the Drosophila protein Groucho, a transcriptional corepressor that lacks DNA-binding activity on its own but can act in concert with other proteins to regulate embryologic development of the fly. Expression of both Grg2 and Grg6 was upregulated 10- to 50-fold by E2A-HLF. Immunoblot analysis detected increased amounts of two additional Groucho-related proteins, Grg1 and Grg4, in cells expressing E2A-HLF. A mutant E2A-HLF protein with a disabled DNA-binding region also mediated pro-B cell survival and activated Groucho-related genes. Among the transcription factors known to interact with Groucho-related protein, only RUNX1 was appreciably downregulated by E2A-HLF. Our results identify a highly conserved family of transcriptional corepressors that are activated by E2A-HLF, and they suggest that downregulation of RUNX1 may contribute to E2A-HLF-mediated leukemogenesis.
- Published
- 2001
- Full Text
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9. SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein.
- Author
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Inukai T, Inoue A, Kurosawa H, Goi K, Shinjyo T, Ozawa K, Mao M, Inaba T, and Look AT
- Subjects
- Animals, Apoptosis, Base Sequence, Basic-Leucine Zipper Transcription Factors, Binding Sites, Cell Survival, Consensus Sequence, DNA-Binding Proteins genetics, Humans, Leukemia, B-Cell metabolism, Mice, Models, Genetic, Multigene Family, Protein Binding, Recombinant Proteins metabolism, Snail Family Transcription Factors, Tissue Distribution, Transcription Factors genetics, Tumor Cells, Cultured, Cell Transformation, Neoplastic genetics, DNA-Binding Proteins metabolism, Gene Expression Regulation, Neoplastic, Leukemia, B-Cell genetics, Oncogene Proteins, Fusion metabolism, Transcription Factors metabolism, Zinc Fingers
- Abstract
The E2A-HLF fusion gene transforms human pro-B lymphocytes by interfering with an early step in apoptotic signaling. In a search for E2A-HLF-responsive genes, we identified a zinc finger transcription factor, SLUG, whose product belongs to the Snail family of developmental regulatory proteins. Importantly, SLUG bears close homology to the CES-1 protein of C. elegans, which acts downstream of CES-2 in a neuron-specific cell death pathway. Consistent with the postulated role of CES-1 as an antiapoptotic transcription factor, SLUG was nearly as active as Bcl-2 or Bcl-xL in promoting the survival of IL-3-dependent murine pro-B cells deprived of the cytokine. We conclude that SLUG is an evolutionarily conserved transcriptional repressor whose activation by E2A-HLF promotes the aberrant survival and eventual malignant transformation of mammalian pro-B cells otherwise slated for apoptotic death.
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- 1999
- Full Text
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10. Two candidate downstream target genes for E2A-HLF.
- Author
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Kurosawa H, Goi K, Inukai T, Inaba T, Chang KS, Shinjyo T, Rakestraw KM, Naeve CW, and Look AT
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- Amino Acid Sequence, Annexins genetics, Apoptosis, Cell Line, Cloning, Molecular, Humans, Membrane Proteins biosynthesis, Membrane Proteins chemistry, Molecular Sequence Data, Repetitive Sequences, Amino Acid, Selectins chemistry, Selectins genetics, Transcription Factors genetics, Tumor Cells, Cultured, DNA-Binding Proteins genetics, Genes, Neoplasm, Membrane Proteins genetics, Neoplasm Proteins, Oncogene Proteins, Fusion genetics
- Abstract
The E2A-HLF fusion gene, formed by the t(17;19)(q22;p13) chromosomal translocation, is thought to drive the leukemic transformation of early B-cell precursors by repressing an evolutionarily conserved apoptotic pathway. To test this hypothesis, we sought to identify downstream targets of E2A-HLF in t(17;19)+ pro-B leukemia cells (UOC-B1) that had been transfected with a zinc-inducible vector encoding a dominant-negative suppressor (E2A-HLF[dn]) of the oncoprotein. Representational difference analysis of mRNAs from E2A-HLF(dn)+ UOC-B1 cells grown with (E2A-HLF inactive) or without (E2A-HLF active) the addition of zinc yielded several differentially expressed cDNA fragments that were individually subcloned. Two of the clones, designated F-5 and G-4, hybridized with mRNAs that were upregulated by E2A-HLF. Levels of both transcripts declined sharply within 8 to 12 hours after suppression of E2A-HLF DNA-binding activity, becoming undetectable after 96 hours. The F-5 cDNA was identified as a portion of ANNEXIN VIII, whose product was expressed in promyelocytic leukemia cells and UOC-B1 cells, but not in other leukemic cell lines. A novel full-length cDNA cloned with the G-4 fragment encoded a protein that we have named SRPUL (sushi-repeat protein upregulated in leukemia). It is normally expressed in heart, ovary, and placenta, but could not be detected in leukemic cell lines other than UOC-B1. Neither protein prevented apoptosis in interleukin-3-dependent murine pro-B cells, suggesting that they have paraneoplastic roles in leukemias that express E2A-HLF, perhaps in the disseminated intravascular coagulopathy and hypercalcemia that characterize these cases.
- Published
- 1999
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