458 results on '"Atsushi Iwama"'
Search Results
202. Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE
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Tze Mun, Loo, Fumitaka, Kamachi, Yoshihiro, Watanabe, Shin, Yoshimoto, Hiroaki, Kanda, Yuriko, Arai, Yaeko, Nakajima-Takagi, Atsushi, Iwama, Tomoaki, Koga, Yukihiko, Sugimoto, Takayuki, Ozawa, Masaru, Nakamura, Miho, Kumagai, Koichi, Watashi, Makoto M, Taketo, Tomohiro, Aoki, Shuh, Narumiya, Masanobu, Oshima, Makoto, Arita, Eiji, Hara, and Naoko, Ohtani
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Lipopolysaccharides ,Male ,Carcinoma, Hepatocellular ,Liver Neoplasms ,Dinoprostone ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,Teichoic Acids ,Tumor Microenvironment ,Animals ,Humans ,Female ,Tumor Escape ,Obesity - Abstract
Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E
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- 2016
203. Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression
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Pu Zhang, Atsushi Iwama, Meritxell Alberich-Jorda, Maria Cristina Magli, Junyan Zhang, Daniel G. Tenen, Christopher J. Hetherington, Henry Yang, Min Ye, Daniela S. Basseres, Thomas W. Davis, Kol Jia Yong, Elena Levantini, Lorena Lobo de Figueiredo-Pontes, Bing Lim, Alain C. Borczuk, Hong Zhang, Giorgia Maroni, Ross A. Soo, Wen Cai Zhang, Benedict Yan, Balazs Halmos, Liangxian Cao, Donna Neuberg, Nadiya Sydorenko, Robert S. Welner, Olivier Kocher, Young Choon Moon, Chiara Battelli, Karen B. O'Brien, Lyuba Varticovski, and Bhavin Thakkar
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,xenograft mice ,cebpa tumor suppressor ,Adenocarcinoma of Lung ,macromolecular substances ,Tumor initiation ,Adenocarcinoma ,transgenic mice ,Biology ,Article ,novel therapeutic treatment for lung cancer ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Proto-Oncogene Proteins ,Internal medicine ,Enhancer binding ,CCAAT-Enhancer-Binding Protein-alpha ,medicine ,Animals ,Humans ,Lung cancer ,Transcription factor ,Mice, Knockout ,Polycomb Repressive Complex 1 ,preclinical murine models of disease ,Regulation of gene expression ,BMI1 oncogene as novel therapeutic target in lung cancer ,knock out mice ,Cancer ,in vivo drug treatment ,General Medicine ,medicine.disease ,PROLIFERAÇÃO CELULAR ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,BMI1 ,030220 oncology & carcinogenesis ,Mutation ,Cancer research - Abstract
Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein α) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPα suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPα expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPα expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPα deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPα-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPα is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPα loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPα and high BMI1.
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- 2016
204. Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome
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Atsushi Iwama, Chiaki Nakaseko, Tomoya Muto, Motohiko Oshima, Kazuya Shimoda, Changshan Wang, Kotaro Yokote, Shuhei Koide, Atsunori Saraya, Nagisa Hasegawa, Kiyoko Takane, Atsushi Kaneda, Goro Sashida, and Hirotaka Matsui
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0301 basic medicine ,Cancer Research ,Mice, Transgenic ,macromolecular substances ,Biology ,Dioxygenases ,Epigenesis, Genetic ,03 medical and health sciences ,Mice ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Animals ,Enhancer of Zeste Homolog 2 Protein ,Epigenetics ,Nucleotide Motifs ,Epigenomics ,Genetics ,Regulation of gene expression ,Mice, Knockout ,Binding Sites ,Base Sequence ,EZH2 ,Hematology ,Epigenome ,DNA Methylation ,Hematopoiesis ,DNA-Binding Proteins ,Repressor Proteins ,Disease Models, Animal ,030104 developmental biology ,Enhancer Elements, Genetic ,Oncology ,CpG site ,Gene Expression Regulation ,Myelodysplastic Syndromes ,DNA methylation ,Cancer research ,CpG Islands ,Stem cell ,Protein Binding ,Transcription Factors - Abstract
Somatic inactivating mutations in epigenetic regulators are frequently found in combination in myelodysplastic syndrome (MDS). However, the mechanisms by which combinatory mutations in epigenetic regulators promote the development of MDS remain unknown. Here we performed epigenomic profiling of hematopoietic progenitors in MDS mice hypomorphic for Tet2 following the loss of the polycomb-group gene Ezh2 (Tet2KD/KDEzh2Δ/Δ). Aberrant DNA methylation propagated in a sequential manner from a Tet2-insufficient state to advanced MDS with deletion of Ezh2. Hyper-differentially methylated regions (hyper-DMRs) in Tet2KD/KDEzh2Δ/Δ MDS hematopoietic stem/progenitor cells were largely distinct from those in each single mutant and correlated with transcriptional repression. Although Tet2 hypomorph was responsible for enhancer hypermethylation, the loss of Ezh2 induced hyper-DMRs that were enriched for CpG islands of polycomb targets. Notably, Ezh2 targets largely lost the H3K27me3 mark while acquiring a significantly higher level of DNA methylation than Ezh1 targets that retained the mark. These findings indicate that Ezh2 targets are the major targets of the epigenetic switch in MDS with Ezh2 insufficiency. Our results provide a detailed trail for the epigenetic drift in a well-defined MDS model and demonstrate that the combined dysfunction of epigenetic regulators cooperatively remodels the epigenome in the pathogenesis of MDS.
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- 2016
205. Histone lysine methyltransferase G9a is a novel epigenetic target for the treatment of hepatocellular carcinoma
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Naoya Mimura, Masayuki Yokoyama, Tomoko Saito, Atsushi Iwama, Masanori Inoue, Tetsuhiro Chiba, Motohiko Oshima, Satoru Miyagi, Yoh Zen, Yoshihiko Ooka, Yoshiko Noguchi, Shiro Tara, Masayuki Otsuka, Atsunori Saraya, Toru Wakamatsu, Akinobu Tawada, Shuhei Koide, Osamu Yokosuka, Kaori Yuki, Sadahisa Ogasawara, Eiichiro Suzuki, Yuko Kusakabe, Masaru Miyazaki, and Kazumasa Aoyama
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0301 basic medicine ,Male ,Pathology ,epithelial mesenchymal transition ,Mice, SCID ,Epigenesis, Genetic ,Histones ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,Histocompatibility Antigens ,Enzyme Inhibitors ,Aged, 80 and over ,Liver Neoplasms ,Azepines ,hepatocellular carcinoma ,Middle Aged ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Female ,Research Paper ,Adult ,medicine.medical_specialty ,Chromatin Immunoprecipitation ,Carcinoma, Hepatocellular ,G9a ,Blotting, Western ,Real-Time Polymerase Chain Reaction ,BIX-01294 ,03 medical and health sciences ,Histone H3 ,medicine ,Animals ,Humans ,Epigenetics ,Epithelial–mesenchymal transition ,Aged ,epigenetics ,Cell growth ,business.industry ,Histone-Lysine N-Methyltransferase ,DNA Methylation ,medicine.disease ,Molecular medicine ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Cancer research ,Quinazolines ,business ,Chromatin immunoprecipitation ,Transforming growth factor - Abstract
// Masayuki Yokoyama 1, * , Tetsuhiro Chiba 1, * , Yoh Zen 2 , Motohiko Oshima 3 , Yuko Kusakabe 1 , Yoshiko Noguchi 1 , Kaori Yuki 1, 3 , Shuhei Koide 3 , Shiro Tara 3 , Atsunori Saraya 3 , Kazumasa Aoyama 3 , Naoya Mimura 3 , Satoru Miyagi 3 , Masanori Inoue 1 , Toru Wakamatsu 1 , Tomoko Saito 1 , Sadahisa Ogasawara 1 , Eiichiro Suzuki 1 , Yoshihiko Ooka 1 , Akinobu Tawada 1 , Masayuki Otsuka 4 , Masaru Miyazaki 4 , Osamu Yokosuka 1 , Atsushi Iwama 3 1 Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan 2 Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan 3 Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 4 Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan * These authors contributed equally to this work Correspondence to: Tetsuhiro Chiba, email: techiba@faculty.chiba-u.jp Keywords: epigenetics, hepatocellular carcinoma, G9a, BIX-01294, epithelial mesenchymal transition Received: May 22, 2016 Accepted: January 27, 2017 Published: February 20, 2017 ABSTRACT Histone H3 lysine 9 dimethylation (H3K9me2) is mainly regulated by the histone lysine methyltransferase G9a and is associated with the repression of transcription. However, both the role of G9a and the significance of H3K9me2 in hepatocellular carcinoma (HCC) cells remain unclear. In this study, we conducted loss-of-function assay of G9a using short-hairpin RNA and pharmacological interference. Knockdown of G9a reduced H3K9me2 levels and impaired both HCC cell growth and sphere formation. However, transforming growth factor β1-induced epithelial mesenchymal transition (EMT) was not suppressed by G9a knockdown. Combined analyses of chromatin immunoprecipitation followed by sequencing and RNA-sequencing led to successful identification of 96 candidate epigenetic targets of G9a. Pharmacological inhibition of G9a by BIX-01294 resulted in both cell growth inhibition and induction of apoptosis in HCC cells. Intraperitoneal administration of BIX-01294 suppressed the growth of xenograft tumors generated by implantation of HCC cells in non-obese diabetic/severe combined immunodeficient mice. Immunohistochemical analyses revealed high levels of G9a and H3K9me2 in 36 (66.7%) and 35 (64.8%) primary HCC tissues, respectively. G9a expression levels were significantly positively correlated with H3K9me2 levels in tumor tissues. In contrast, in non-tumor tissues, G9a and H3K9me2 were only observed in biliary epithelial cells and periportal hepatocytes. In conclusion, G9a inhibition impairs anchorage-dependent and -independent cell growth, but not EMT in HCC cells. Our data indicate that pharmacological interference of G9a might be a novel epigenetic approach for the treatment of HCC.
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- 2016
206. Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction
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Hiroshi Akazawa, Yoshio Kobayashi, Mei Lan Liu, Issei Komuro, Toshinao Takahashi, Atsuhiko T. Naito, Atsushi Iwama, Toshio Nagai, Naomichi Kondou, Goro Sashida, and Masato Kanda
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0301 basic medicine ,Cellular differentiation ,Myocardial Infarction ,lcsh:Medicine ,Leukemia Inhibitory Factor ,Mice ,Phosphatidylinositol 3-Kinases ,Spectrum Analysis Techniques ,Heart Regeneration ,Medicine and Health Sciences ,Morphogenesis ,Myocyte ,Myocytes, Cardiac ,Cell Cycle and Cell Division ,lcsh:Science ,Staining ,Multidisciplinary ,Kinase ,Stem Cells ,Cell Staining ,Heart ,Cell Differentiation ,Flow Cytometry ,MAP Kinase Kinase Kinases ,Specimen preparation and treatment ,STAT Transcription Factors ,Cell Processes ,Spectrophotometry ,Cytophotometry ,Stem cell ,Anatomy ,Research Article ,MAP Kinase Signaling System ,Cardiology ,Mice, Transgenic ,Biology ,03 medical and health sciences ,Side population ,Precursor cell ,Regeneration ,Animals ,Cell Proliferation ,Janus Kinases ,Myocardium ,lcsh:R ,DAPI staining ,Biology and Life Sciences ,Cell Biology ,Molecular biology ,Research and analysis methods ,Disease Models, Animal ,030104 developmental biology ,Nuclear staining ,Cardiovascular Anatomy ,lcsh:Q ,Janus kinase ,Leukemia inhibitory factor ,Organism Development ,Proto-Oncogene Proteins c-akt ,Developmental Biology - Abstract
Cardiac stem cells or precursor cells regenerate cardiomyocytes; however, the mechanism underlying this effect remains unclear. We generated CreLacZ mice in which more than 99.9% of the cardiomyocytes in the left ventricular field were positive for 5-bromo-4-chloro-3-indolyl-β-d-galactoside (X-gal) staining immediately after tamoxifen injection. Three months after myocardial infarction (MI), the MI mice had more X-gal-negative (newly generated) cells than the control mice (3.04 ± 0.38/mm2, MI; 0.47 ± 0.16/mm2, sham; p < 0.05). The cardiac side population (CSP) cell fraction contained label-retaining cells, which differentiated into X-gal-negative cardiomyocytes after MI. We injected a leukemia inhibitory factor (LIF)-expression construct at the time of MI and identified a significant functional improvement in the LIF-treated group. At 1 month after MI, in the MI border and scar area, the LIF-injected mice had 31.41 ± 5.83 X-gal-negative cardiomyocytes/mm2, whereas the control mice had 12.34 ± 2.56 X-gal-negative cardiomyocytes/mm2 (p < 0.05). Using 5-ethynyl-2'-deoxyurinide (EdU) administration after MI, the percentages of EdU-positive CSP cells in the LIF-treated and control mice were 29.4 ± 2.7% and 10.6 ± 3.7%, respectively, which suggests that LIF influenced CSP proliferation. Moreover, LIF activated the Janus kinase (JAK)signal transducer and activator of transcription (STAT), mitogen-activated protein kinase/extracellular signal-regulated (MEK)extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)-AKT pathways in CSPs in vivo and in vitro. The enhanced green fluorescent protein (EGFP)-bone marrow-chimeric CreLacZ mouse results indicated that LIF did not stimulate cardiogenesis via circulating bone marrow-derived cells during the 4 weeks following MI. Thus, LIF stimulates, in part, stem cell-derived cardiomyocyte regeneration by activating cardiac stem or precursor cells. This approach may represent a novel therapeutic strategy for cardiogenesis.
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- 2016
207. Circulating soluble LR11/SorLA levels are highly increased and ameliorated by chemotherapy in acute leukemias
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Yasunori Sato, Naomi Shimizu, Atsushi Iwama, Masahiro Takeuchi, Koutaro Yokote, Yasushi Saito, Hideaki Bujo, Shio Sakai, Meizi Jiang, Hiroyuki Ebinuma, Chiaki Nakaseko, Wolfgang J. Schneider, Chikako Ohwada, Takeharu Kawaguchi, Isamu Fukamachi, and Shokichi Tsukamoto
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Myeloid ,Clinical Biochemistry ,Gene Expression ,Antineoplastic Agents ,Enzyme-Linked Immunosorbent Assay ,Real-Time Polymerase Chain Reaction ,Biochemistry ,Monocytes ,Flow cytometry ,Cell Line, Tumor ,hemic and lymphatic diseases ,Biomarkers, Tumor ,Humans ,Medicine ,LDL-Receptor Related Proteins ,Acute leukemia ,medicine.diagnostic_test ,business.industry ,Monocyte ,Remission Induction ,Biochemistry (medical) ,Membrane Transport Proteins ,Myeloid leukemia ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Flow Cytometry ,medicine.disease ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,medicine.anatomical_structure ,Solubility ,Immunology ,Stem cell ,business - Abstract
LR11/SorLA, a receptor interacting with CD87 on monocytes and macrophages, is highly expressed on human immature hematopoietic stem cells. However, it is unknown whether LR11 is expressed on premature leukemic cells, and whether the levels of circulating soluble LR11 (sLR11) shed from leukemic cells correlate with disease state.The expression of LR11 on leucocytes and leukemic cells was examined by flow cytometry. Serum sLR11 levels were measured by ELISA in patients with various hematological diseases, including 43 acute myeloid leukemia (AML) and 23 acute lymphoblastic leukemia (ALL) patients. Data were subjected to statistical analysis for validation of sLR11 levels and patients' clinical data.LR11 is specifically expressed in monocytes, and surface levels on leukemic cells are highly induced in both AML and ALL. sLR11 levels of acute leukemia patients were significantly increased (P0.001) (ALL, 73.5±93.5 ng/ml; AML, 26.8±29.1 ng/ml) in comparison to controls (9.2±3.3 ng/ml). Patients with AML and ALL in remission showed significantly decreased sLR11 levels to below 20 ng/ml.LR11 and its released soluble form are strongly elevated in acute leukemias. Remarkably, this increase in circulating sLR11 levels is ameliorated at complete remission.
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- 2012
208. Aldehyde dehydrogenase 1 is associated with recurrence-free survival but not stem cell-like properties in hepatocellular carcinoma
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Fumihiko Kanai, Atsushi Iwama, Masaru Miyazaki, Motohisa Tada, Satoru Miyagi, Eiichiro Suzuki, Fumio Imazeki, Osamu Yokosuka, Tetsuhiro Chiba, and Yoh Zen
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Gene knockdown ,Hepatology ,Cell growth ,Epithelial cell adhesion molecule ,Biology ,Stem cell marker ,medicine.disease ,Molecular biology ,digestive system diseases ,chemistry.chemical_compound ,Infectious Diseases ,chemistry ,Cancer stem cell ,Hepatocellular carcinoma ,medicine ,Immunohistochemistry ,Stem cell - Abstract
AIM It has been reported that aldehyde dehydrogenase 1 A1 (ALDH1) could be not only a normal stem cell marker but also a cancer stem cell marker. ALDH1 expression could be a predictor of poor prognosis in a wide range of cancers. However, the role of ALDH1 in hepatocellular carcinoma (HCC) remains unclear. METHOD We conducted loss-of-function assays for ALDH1 by using short-hairpin RNA in HCC cells and evaluated the correlation between ALDH1 expression and clinicopathological features based on immunohistochemical assessment of 49 primary HCC tissues. RESULTS Neither cell proliferation nor the anchorage-independent sphere formation ability of HCC cells were altered after ALDH1 knockdown. Flow cytometric analyses revealed that ALDH1 knockdown showed no remarkable change in the proportion of epithelial cell adhesion molecule (EpCAM)(+) tumor-initiating cells. Although non-tumor tissues in primary HCC samples diffusely and homogenously expressed ALDH1 at low levels, tumor tissues contained cells with high levels of ALDH1 expression at varying frequencies. Primary HCC samples were categorized as ALDH1-high or ALDH1-low based on the percentage of ALDH1-overexpressing cells. ALDH1-high HCC was characterized by low serum levels of α-fetoprotein (P
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- 2012
209. Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes
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Hitoshi Ichikawa, Satomi Tanaka, Makiko Mochizuki-Kashio, Atsushi Iwama, Jin Yuan, Hideyuki Oguro, Satoru Miyagi, Satoshi Yamazaki, Haruhiko Koseki, and Hiromitsu Nakauchi
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Immunology ,Polycomb-Group Proteins ,macromolecular substances ,Biology ,Thrombopoiesis ,Mice ,Proto-Oncogene Proteins ,Polycomb-group proteins ,medicine ,Animals ,Immunology and Allergy ,Genes, Tumor Suppressor ,Cyclin-Dependent Kinase Inhibitor p16 ,DNA Primers ,Megakaryocytopoiesis ,Mice, Knockout ,Polycomb Repressive Complex 1 ,Base Sequence ,fungi ,HMGA2 Protein ,EZH2 ,Brief Definitive Report ,Nuclear Proteins ,Hematopoietic Stem Cells ,medicine.disease ,Extramedullary hematopoiesis ,Mice, Inbred C57BL ,Repressor Proteins ,Disease Models, Animal ,Haematopoiesis ,Primary Myelofibrosis ,BMI1 ,Hematopoiesis, Extramedullary ,Cancer research ,Stem cell ,Chromatin immunoprecipitation - Abstract
Polycomb group gene Bmi1 functions as a tumor suppressor in myelofibrosis., Polycomb-group (PcG) proteins form the multiprotein polycomb repressive complexes (PRC) 1 and 2, and function as transcriptional repressors through histone modifications. They maintain the proliferative capacity of hematopoietic stem and progenitor cells by repressing the transcription of tumor suppressor genes, namely Ink4a and Arf, and thus have been characterized as oncogenes. However, the identification of inactivating mutations in the PcG gene, EZH2, unveiled a tumor suppressor function in myeloid malignancies, including primary myelofibrosis (PMF). Here, we show that loss of another PcG gene, Bmi1, causes pathological hematopoiesis similar to PMF. In a mouse model, loss of Bmi1 in Ink4a-Arf−/− hematopoietic cells induced abnormal megakaryocytopoiesis accompanied by marked extramedullary hematopoiesis, which eventually resulted in lethal myelofibrosis. Absence of Bmi1 caused derepression of a cohort of genes, including Hmga2, which is an oncogene overexpressed in PMF. Chromatin immunoprecipitation assays revealed that Bmi1 directly represses the transcription of Hmga2. Overexpression of Hmga2 in hematopoietic stem cells induced a myeloproliferative state with enhanced megakaryocytopoiesis in mice, implicating Hmga2 in the development of pathological hematopoiesis in the absence of Bmi1. Our findings provide the first genetic evidence of a tumor suppressor function of Bmi1 and uncover the role of PcG proteins in restricting growth by silencing oncogenes.
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- 2012
210. [Mutations of epigenetic regulator genes and myeloid malignancies]
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Tomoya, Muto, Goro, Sashida, Motohiko, Oshima, and Atsushi, Iwama
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Transcription, Genetic ,Gene Expression Regulation, Leukemic ,Leukemia, Myeloid ,Mutation ,Animals ,Humans ,DNA Methylation ,Epigenesis, Genetic - Abstract
Recent genome studies have identified recurrent somatic mutations in various myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasm. These mutations frequently occur in epigenetic regulator genes, and functions of the proteins encoded by these genes in hematopoietic cells have been extensively analyzed, as reported recently. It is noteworthy that several epigenetic regulator genes, such as DNMT3A, TET2 and ASXL1, have also been identified in pre-leukemic stem cells. As targeting pre-leukemic stem cells would be a promising therapeutic approach, further investigations of epigenetic abnormalities in hematopoietic cells are anticipated to lead to the development of novel epigenetic therapies. In this review, we discuss recent genetic and functional data regarding epigenetic regulator genes and the future landscape of this new research field.
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- 2015
211. Loss of Pcgf5 Affects Global H2A Monoubiquitination but Not the Function of Hematopoietic Stem and Progenitor Cells
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Atsushi Iwama, Kazumasa Aoyama, Manabu Nakayama, Tomoyuki Ishikura, Yaeko Nakajima-Takagi, Sha Si, Hiroki Sugishita, Motohiko Oshima, Haruhiko Koseki, and Atsunori Saraya
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0301 basic medicine ,Myeloid ,Cellular differentiation ,lcsh:Medicine ,Gene Expression ,Histones ,Mice ,Spectrum Analysis Techniques ,Animal Cells ,Medicine and Health Sciences ,Blood and Lymphatic System Procedures ,Monoubiquitination ,lcsh:Science ,Bone Marrow Transplantation ,Regulation of gene expression ,Polycomb Repressive Complex 1 ,Multidisciplinary ,Stem Cells ,Cell Differentiation ,Animal Models ,Hematology ,Flow Cytometry ,Precipitation Techniques ,Haematopoiesis ,medicine.anatomical_structure ,Spectrophotometry ,Cytophotometry ,Stem cell ,Cellular Types ,Protein Binding ,Research Article ,Chromatin Immunoprecipitation ,Genotype ,Mouse Models ,Surgical and Invasive Medical Procedures ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,Histone H2A ,medicine ,Genetics ,Animals ,Immunoprecipitation ,Gene Regulation ,Progenitor cell ,Transplantation ,lcsh:R ,Ubiquitination ,Biology and Life Sciences ,Cell Biology ,Hematopoietic Stem Cells ,Molecular biology ,Hematopoiesis ,Mice, Inbred C57BL ,030104 developmental biology ,lcsh:Q - Abstract
Polycomb-group RING finger proteins (Pcgf1-Pcgf6) are components of Polycomb repressive complex 1 (PRC1)-related complexes that catalyze monoubiquitination of histone H2A at lysine 119 (H2AK119ub1), an epigenetic mark associated with repression of genes. Pcgf5 has been characterized as a component of PRC1.5, one of the non-canonical PRC1, consisting of Ring1a/b, Rybp/Yaf2 and Auts2. However, the biological functions of Pcgf5 have not yet been identified. Here we analyzed the impact of the deletion of Pcgf5 specifically in hematopoietic stem and progenitor cells (HSPCs). Pcgf5 is expressed preferentially in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) compared with committed myeloid progenitors and differentiated cells. We transplanted bone marrow (BM) cells from Rosa::Cre-ERT control and Cre-ERT;Pcgf5fl/fl mice into lethally irradiated recipient mice. At 4 weeks post-transplantation, we deleted Pcgf5 by injecting tamoxifen, however, no obvious changes in hematopoiesis were detected including the number of HSPCs during a long-term observation period following the deletion. Competitive BM repopulating assays revealed normal repopulating capacity of Pcgf5-deficient HSCs. Nevertheless, Pcgf5-deficient HSPCs showed a significant reduction in H2AK119ub1 levels compared with the control. ChIP-sequence analysis confirmed the reduction in H2AK119ub1 levels, but revealed no significant association of changes in H2AK119ub1 levels with gene expression levels. Our findings demonstrate that Pcgf5-containing PRC1 functions as a histone modifier in vivo, but its role in HSPCs is limited and can be compensated by other PRC1-related complexes in HSPCs.
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- 2015
212. Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells
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Changshan Wang, Atsunori Saraya, Atsushi Iwama, George R. Wendt, Tomoya Muto, Shuhei Koide, Yutaka Suzuki, Motohiko Oshima, Satoru Miyagi, Makiko Mochizuki-Kashio, Nagisa Hasegawa, Kazuya Shimoda, and Shogo Yabata
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0301 basic medicine ,Cancer Research ,Mice, Transgenic ,macromolecular substances ,Biology ,LIN28 ,Models, Biological ,03 medical and health sciences ,Mice ,Genetics ,medicine ,Animals ,Enhancer of Zeste Homolog 2 Protein ,Lymphopoiesis ,Gene Silencing ,Progenitor cell ,Molecular Biology ,Regulation of gene expression ,Gene Expression Profiling ,Polycomb Repressive Complex 2 ,Computational Biology ,RNA-Binding Proteins ,Cell Biology ,Hematology ,Gene signature ,Hematopoietic Stem Cells ,Haematopoiesis ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Hematologic Neoplasms ,Cancer research ,Disease Progression ,RNA Interference ,Bone marrow ,Stem cell ,Transcriptome - Abstract
Fetal liver hematopoietic stem cells (HSCs) seed bone marrow (BM) and undergo reprograming into adult-type HSCs that are largely quiescent and restricted in their self-renewal activity. Here we report that in the absence of the polycomb-group gene Ezh2, a cohort of fetal-specific genes, including let-7 target genes, were activated in BM hematopoietic stem/progenitor cells (HSPCs), leading to acquisition of fetal phenotypes by BM HSPCs, such as enhanced self-renewal activity and production of fetal-type lymphocytes. The Lin28b/let-7 pathway determines developmentally timed changes in HSPC programs. Of note, many of the fetal-specific let-7 target genes, including Lin28, appear to be transcriptionally repressed by Ezh2-mediated H3K27me3 in BM HSPCs, and Ezh2 loss results in their ectopic expression, particularly in hematologic malignancies that develop in the absence of Ezh2. These findings suggest that Ezh2 cooperates with let-7 microRNAs in silencing the fetal gene signature in BM HSPCs and restricts their transformation.
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- 2015
213. Direct activation of STAT5 by ETV6-LYN fusion protein promotes induction of myeloproliferative neoplasm with myelofibrosis
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Masahiro Takeuchi, Satomi Tanaka, Naoto Yamaguchi, Atsunori Saraya, Atsushi Iwama, Lothar Hennighausen, Hiroaki Tanaka, Emiko Sakaida, Makiko Yui, Koutaro Yokote, Changshan Wang, Yusuke Takeda, Satoru Miyagi, Chikako Ohwada, and Chiaki Nakaseko
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biology ,food and beverages ,hemic and immune systems ,Hematology ,medicine.disease ,environment and public health ,ETV6 ,Haematopoiesis ,Myeloproliferative Disorders ,LYN ,hemic and lymphatic diseases ,medicine ,biology.protein ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Stem cell ,Myelofibrosis ,Myeloproliferative neoplasm ,STAT5 - Abstract
Myeloproliferative neoplasms (MPN), a group of haematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. We previously identified the fusion of the ETV6 gene to the LYN gene (ETV6-LYN) in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of ETV6-LYN into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged LYN kinase in the pathogenesis of MPN with myelofibrosis. However, the signalling molecules directly downstream from and activated by ETV6-LYN remain unknown. In this study, we demonstrated that the direct activation of STAT5 by ETV6-LYN is crucial for the development of MPN. ETV6-LYN was constitutively active as a kinase through autophosphorylation. ETV6-LYN, but not its kinase-dead mutant, supported cytokine-free proliferation of haematopoietic cells. STAT5 was activated in a JAK2-independent manner in ETV6-LYN-expressing cells. ETV6-LYN interacted with STAT5 and directly activated STAT5 both in vitro and in vivo. Of note, ETV6-LYN did not support the formation of colonies by Stat5-deficient HSCs under cytokine-free conditions and the capacity of ETV6-LYN to induce MPN with myelofibrosis was profoundly attenuated in a Stat5-null background. These findings define STAT5 as a direct target of ETV6-LYN and unveil the LYN-STAT5 axis as a novel pathway to augment proliferative signals in MPN and leukaemia.
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- 2011
214. Genome-wide analysis of target genes regulated by HoxB4 in hematopoietic stem and progenitor cells developing from embryonic stem cells
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Haruhiko Koseki, Mitsuhiro Endoh, Michael Kyba, Atsushi Iwama, Fumihiro Sugiyama, Yaeko Nakajima-Takagi, Takaho A. Endo, Motohiko Oshima, Mitsujiro Osawa, and Tetsuro Toyoda
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LMO2 ,Hematopoiesis and Stem Cells ,Immunology ,Biology ,Biochemistry ,Cell Line ,Mice ,chemistry.chemical_compound ,Proto-Oncogene Proteins ,Databases, Genetic ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Animals ,Progenitor cell ,Embryonic Stem Cells ,T-Cell Acute Lymphocytic Leukemia Protein 1 ,Oligonucleotide Array Sequence Analysis ,Homeodomain Proteins ,GATA2 ,Gene Expression Regulation, Developmental ,Cell Biology ,Hematology ,Hematopoietic Stem Cells ,Embryonic stem cell ,DNA-Binding Proteins ,GATA2 Transcription Factor ,Haematopoiesis ,medicine.anatomical_structure ,RUNX1 ,chemistry ,Core Binding Factor Alpha 2 Subunit ,Cancer research ,Bone marrow ,Stem cell ,Genome-Wide Association Study ,Transcription Factors - Abstract
Forced expression of the transcription factor HoxB4 has been shown to enhance the self-renewal capacity of mouse bone marrow hematopoietic stem cells (HSCs) and confer a long-term repopulating capacity to yolk sac and embryonic stem (ES) cell–derived hematopoietic precursors. The fact that ES cell–derived precursors do not repopulate bone marrow without HoxB4 underscores an important role for HoxB4 in the maturation of ES-derived hematopoietic precursors into long-term repopulating HSCs. However, the precise molecular mechanism underlying this process is barely understood. In this study, we performed a genome-wide analysis of HoxB4 using ES cell–derived hematopoietic stem/progenitor cells. The results revealed many of the genes essential for HSC development to be direct targets of HoxB4, such as Runx1, Scl/Tal1, Gata2, and Gfi1. The expression profiling also showed that HoxB4 indirectly affects the expression of several important genes, such as Lmo2, Erg, Meis1, Pbx1, Nov, AhR, and Hemgn. HoxB4 tended to activate the transcription, but the down-regulation of a significant portion of direct targets suggested its function to be context-dependent. These findings indicate that HoxB4 reprograms a set of key regulator genes to facilitate the maturation of developing HSCs into repopulating cells. Our list of HoxB4 targets also provides novel candidate regulators for HSCs.
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- 2011
215. Diploid, not polyploid: new platelet producers
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Eriko Nitta and Atsushi Iwama
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medicine.medical_specialty ,Immunology ,Cell ,Population ,Biochemistry ,Polyploidy ,Polyploid ,Animals ,Medicine ,Cell Lineage ,Platelet ,Yolk sac ,education ,Megakaryocyte Progenitor Cells ,education.field_of_study ,business.industry ,Embryo ,Cell Biology ,Hematology ,Embryo, Mammalian ,Diploidy ,Surgery ,Cell biology ,medicine.anatomical_structure ,embryonic structures ,Hematopoietic progenitor cells ,Ploidy ,business ,Megakaryocytes - Abstract
In this issue of Blood, Potts et al have identified a unique cell population in the yolk sac (YS) as the source of the first platelet-forming cells in mouse embryos. These cells are diploid and are produced via a pathway independent of hematopoietic progenitor cells (HPCs) generating polyploid megakaryocytes (MKs).1
- Published
- 2014
216. NUP98-HBO1 Induces Clinically Relevant Chronic Myelomonocytic Leukemia Pathogenesis Through Aberrant Histone Acetylation
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Toshio Kitamura, Atsushi Iwama, Issay Kitabayashi, Yuki Kagiyama, Yoshihiro Hayashi, Yuka Harada, Hironori Harada, and Hirotaka Matsui
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Cancer Research ,biology ,business.industry ,Chronic myelomonocytic leukemia ,Cell Biology ,Hematology ,medicine.disease ,Pathogenesis ,Histone ,Acetylation ,Genetics ,medicine ,Cancer research ,biology.protein ,business ,Molecular Biology - Published
- 2018
217. PLZF Regulates Enhancer Activity during Hematopoietic Aging
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Atsushi Iwama, Mathilde Poplineau, Estelle Duprez, Andrew J. Saurin, Julien Vernerey, and Nadine Platet
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Cancer Research ,Haematopoiesis ,Genetics ,Cell Biology ,Hematology ,Biology ,Enhancer ,Molecular Biology ,Cell biology - Published
- 2018
218. PRC1.1, a Variant Polycomb Repressive Complex 1 in Normal and Malignant Hematopoiesis
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Atsushi Iwama
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Cancer Research ,Haematopoiesis ,Genetics ,Cancer research ,Cell Biology ,Hematology ,Biology ,PRC1 ,Molecular Biology - Published
- 2018
219. Metabolic Regulation of Hematopoietic Stem Cells by O-Linked N-Acetylglucosamine Transferase
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Yumi Fukuchi, Kiichi Yanagisawa, Hiroyoshi Kunimoto, Shunsuke Soma, Koichi Murakami, Atsushi Iwama, Daisuke Kurotaki, Yoshitoshi Atobe, Hiroshi Kobayashi, Shinichiro Okamoto, Miho Haraguchi, Noriyo Hayakawa, Wataru Kawase, Hideaki Nakajima, Takako Hishiki, Kengo Funakoshi, Shuhei Koide, Minoru S.H. Ko, Ryusuke Yoshimi, Mayumi Oda, Tomohiko Tamura, Motohiko Oshima, Keiyo Takubo, and Tomomi Matsuura
- Subjects
O-LINKED N-ACETYLGLUCOSAMINE TRANSFERASE ,Cancer Research ,Haematopoiesis ,Metabolic regulation ,Chemistry ,Genetics ,Cell Biology ,Hematology ,Stem cell ,Molecular Biology ,Molecular biology - Published
- 2018
220. Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells
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Yoshiaki Kubota, Atsushi Iwama, Motohiko Oshima, Yaeko Nakajima-Takagi, Satoshi Yamazaki, Keiyo Takubo, Li-Bo Hou, Atsunori Saraya, Tohru Minamino, Takahito Iga, Mayoko Tsuji, Sha Si, and Shuhei Koide
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0301 basic medicine ,Cancer Research ,Stromal cell ,Endothelium ,Inflammation ,Mice ,03 medical and health sciences ,Animals, Congenic ,Bone Marrow ,Genetics ,medicine ,Animals ,Stem Cell Niche ,Molecular Biology ,Mice, Knockout ,biology ,Mesenchymal stem cell ,Endothelial Cells ,Mesenchymal Stem Cells ,Proto-Oncogene Proteins c-mdm2 ,Cell Biology ,Hematology ,Genes, p53 ,Hematopoietic Stem Cells ,Blood Cell Count ,Cell biology ,Mice, Inbred C57BL ,Radiation Injuries, Experimental ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,biology.protein ,Mdm2 ,Endothelium, Vascular ,Fluorouracil ,Bone marrow ,Tumor Suppressor Protein p53 ,medicine.symptom ,Stem cell - Abstract
Hematopoietic stem cells (HSCs) are exposed to various insults such as genotoxic stress, inflammation, and infection, which have a direct effect. These insults deplete, cause a functional decline in, and promote HSC aging and transformation. However, the impact of hematopoietic insults on niche cells remains largely unknown. We have reported previously that p53 is activated in blood vessels by various stresses, including hypoxia, inflammation, and aging, and contributes to tissue dysfunction and metabolic abnormalities. We hypothesized that hematopoietic insults also affect the bone marrow (BM) vascular niche. Here, we demonstrate that p53 becomes activated in BM endothelial cells upon hematopoietic stresses such as irradiation and chemotherapeutic treatments. The conditional activation of p53 in VE-cadherin+ vascular niche cells by deleting Mdm2 induces the expression of p53 target genes specifically in vascular endothelial cells, resulting in the dilation and collapse of vascular endothelial cells and reductions in perivascular mesenchymal stromal cell numbers. Consequently, hematopoietic stem cells (HSCs) fail to maintain dormancy, mobilize to the periphery, and are depleted significantly. Our results indicate that various hematopoietic insults affect HSCs, not only directly, but also indirectly by altering vascular integrity, which is critical for perivascular niche formation and maintenance of HSCs.
- Published
- 2018
221. Role of the polycomb group proteins in hematopoietic stem cells
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Takaaki Konuma, Atsushi Iwama, and Hideyuki Oguro
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Genetics ,genetic structures ,fungi ,Hematopoietic stem cell ,hemic and immune systems ,macromolecular substances ,Cell Biology ,Biology ,Cell biology ,Chromatin ,medicine.anatomical_structure ,BMI1 ,Polycomb-group proteins ,medicine ,Epigenetics ,Stem cell ,Developmental Biology ,Adult stem cell ,Bivalent chromatin - Abstract
Polycomb group (PcG) proteins play a role in the transcriptional repression of genes through histone modifications. Recent studies have clearly demonstrated that PcG proteins are required for the maintenance of embryonic as well as a broad range of adult stem cells, including hematopoietic stem cells (HSCs). PcG proteins maintain the self-renewal capacity of HSCs by repressing tumor suppressor genes and keep differentiation programs poised for activation in HSCs by repressing a cohort of hematopoietic developmental regulator genes via bivalent chromatin domains. Enforced expression of one of the PcG genes, Bmi1, augments the self-renewal capacity of HSCs. PcG proteins also maintain redox homeostasis to prevent premature loss of HSCs. These findings established PcG proteins as essential regulators of HSCs and underscored epigenetics as a new field of HSC research. In this review, we focus on the role of PcG proteins in the epigenetic regulation of the self-renewal capacity and multipotency of HSCs.
- Published
- 2010
222. The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells
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Osamu Yokosuka, Atsushi Iwama, Takaaki Konuma, Tetsuhiro Chiba, Masamitsu Negishi, Makoto Ogawa, Ryutaro Aoki, Satoru Miyagi, and Hideki Taniguchi
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Cellular differentiation ,Polycomb-Group Proteins ,macromolecular substances ,Biology ,Methylation ,Histones ,Mice ,Pregnancy ,Proto-Oncogene Proteins ,Animals ,Homeostasis ,Enhancer of Zeste Homolog 2 Protein ,Progenitor cell ,Cells, Cultured ,Cyclin-Dependent Kinase Inhibitor p16 ,Mice, Knockout ,Polycomb Repressive Complex 1 ,Hepatocyte differentiation ,Hepatology ,Stem Cells ,Polycomb Repressive Complex 2 ,Nuclear Proteins ,Cell Differentiation ,Histone-Lysine N-Methyltransferase ,Embryonic stem cell ,Mice, Inbred C57BL ,Repressor Proteins ,Endothelial stem cell ,Liver ,BMI1 ,Hepatocytes ,Cancer research ,biology.protein ,ADP-Ribosylation Factor 1 ,Female ,Bile Ducts ,Stem cell ,PRC2 ,Cell Division - Abstract
Background & Aims Polycomb group proteins initiate and maintain gene silencing through chromatin modifications and contribute to the maintenance of self-renewal in a variety of stem cells. Among polycomb repressive complexes (PRCs), PRC2 initiates gene silencing by methylating histone H3 lysine 27, and PRC1 maintains gene silencing through mono-ubiquitination of histone H2A lysine 119. We have previously shown that Bmi1, a core component of PRC1, tightly regulates the self-renewal of hepatic stem/progenitor cells. Methods In this study, we conducted lentivirus-mediated knockdown of Ezh2 to characterise the function of Ezh2, a major component of PRC2, in hepatic stem/progenitor cells. Results Loss of Ezh2 function in embryonic murine hepatic stem/progenitor cells severely impaired proliferation and self-renewal capability. This effect was more prominent than that of Bmi1- knockdown and was partially abrogated by the deletion of both Ink4a and Arf , major targets of PRC1 and PRC2. Importantly, Ezh2- knockdown but not Bmi1- knockdown promoted the differentiation and terminal maturation of hepatocytes, followed by the up-regulation of several transcriptional regulators of hepatocyte differentiation. Conclusions Our findings indicate that Ezh2 plays an essential role in the maintenance of both the proliferative and self-renewal capacity of hepatic stem/progenitor cells and the full execution of their differentiation.
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- 2010
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223. Cancer stem cells in hepatocellular carcinoma: Recent progress and perspective
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Atsushi Iwama, Akihide Kamiya, Osamu Yokosuka, and Tetsuhiro Chiba
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Cancer Research ,Carcinoma, Hepatocellular ,Cellular differentiation ,Population ,Biology ,Models, Biological ,Cancer stem cell ,Carcinoma ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Cell Lineage ,education ,Cell Proliferation ,education.field_of_study ,Cell growth ,Liver Neoplasms ,Cancer ,Cell Differentiation ,medicine.disease ,Oncology ,Hepatocellular carcinoma ,Immunology ,Cancer research ,Neoplastic Stem Cells ,Stem cell - Abstract
Although the "cancer stem cell (CSC)" hypothesis was first proposed roughly 50 years ago, recent progress in stem cell biology and technologies has successfully achieved the identification of CSCs in a variety of cancers. CSCs are defined as a minor population which possesses a prominent ability to generate new tumors that faithfully reproduce the phenotype of original tumors in xenotransplant assays. Additionally, CSCs are able to self-renew and generate differentiated progenies to organize a hierarchical cell system in a similar fashion to normal stem cells. Although not all types of cancer follow the CSC theory, it provides an attractive cellular mechanism to account for the therapeutic resistance and recurrence of the disease. A minor population with CSC properties has been detected in a number of established hepatocellular carcinoma (HCC) cell lines and extensive analyses characterizing the CSC system in primary HCC samples are now ongoing. Considering that HCC has high rates of recurrence and mortality, novel therapeutic approaches are urgently required. Although the clinical relevance of CSCs remains elusive, deep understanding of the cellular organization of HCC may allow us to develop therapies targeting specific cell types such as CSCs.
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- 2009
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224. Distinct expression of polycomb group proteins EZH2 and BMI1 in hepatocellular carcinoma
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Yutaka Yonemitsu, Makoto Arai, Yukio Nakatani, Yuichiro Nagai, Fumio Imazeki, Masaru Miyazaki, Osamu Yokosuka, Ryutaro Aoki, Kenichi Fukai, Atsushi Iwama, Satoru Miyagi, and Tetsuhiro Chiba
- Subjects
Male ,Carcinoma, Hepatocellular ,Polycomb-Group Proteins ,Tetrazolium Salts ,macromolecular substances ,Biology ,Pathology and Forensic Medicine ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Carcinoma ,medicine ,Humans ,Enhancer of Zeste Homolog 2 Protein ,RNA, Small Interfering ,Fluorescent Antibody Technique, Indirect ,Aged ,Cell Proliferation ,Aged, 80 and over ,Polycomb Repressive Complex 1 ,Gene knockdown ,Cell growth ,Liver Neoplasms ,Polycomb Repressive Complex 2 ,Nuclear Proteins ,Cancer ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Molecular biology ,DNA-Binding Proteins ,Repressor Proteins ,Thiazoles ,BMI1 ,Hepatocellular carcinoma ,Cancer research ,Female ,Liver cancer ,Transcription Factors - Abstract
Polycomb gene products play a crucial role in the development of highly malignant phenotypes and aggressive cancer progression in a variety of cancers; however, their role in hepatocellular carcinoma remains unclear. First, we analyzed the impact of EZH2 and BMI1 modulation on cell growth of HepG2 cells. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays revealed marked growth inhibition after EZH2 or BMI1 knockdown. In addition, simultaneous knockdown of these 2 genes further augmented cell growth inhibitory effects. Next, we conducted immunohistochemical assessment of 86 hepatocellular carcinoma surgical specimens, evaluating the correlation between EZH2 and BMI1 protein expression and clinicopathologic features. High-level EZH2 and BMI1 expression was detected in 57 (66.3%) and 52 tumor tissues (60.5%), respectively. Among these, 48 tumor tissues (55.8%) showed colocalization of EZH2 and BMI1 in almost all tumor cells. The cumulative recurrence rate, but not survival rate, was significantly higher in patients positive for EZH2 (P = .029) and BMI1 (P = .039) than in their negative counterparts, as determined by Kaplan-Meier analysis. These data indicate that EZH2 and BMI1 may cooperate in initiation and progression of hepatocellular carcinoma.
- Published
- 2009
225. Identification of a novel TEL–Lyn fusion gene in primary myelofibrosis
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Daijiro Abe, Naomi Shimizu, Hiroaki Tanaka, Yusuke Takeda, Emiko Sakaida, Atsushi Iwama, Shio Sakai, Satoru Miyagi, Chikako Ohwada, Masahiro Takeuchi, Yasushi Saito, and Chiaki Nakaseko
- Subjects
Fusion gene ,Lyn protein-tyrosine kinase ,Hybrid gene ,Cancer Research ,Oncology ,LYN ,medicine ,Cancer research ,Hematology ,Biology ,Myelofibrosis ,medicine.disease - Published
- 2009
226. Tumor Suppression by Phospholipase C-β3 via SHP-1-Mediated Dephosphorylation of Stat5
- Author
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Yuko Kawakami, Yuko Kato, Dianqing Wu, Thomas J. Kipps, Atsushi Iwama, Lothar Hennighausen, Hong Hong, Luigi F. Bertoli, Randall S. Davis, Hiroki Yasudo, Cyrus C. Hsia, Joaquín Madrenas, Wenbin Xiao, Anargyros Xenocostas, Akiko Kimura, Toshiaki Kawakami, Hiromitsu Nakauchi, Hiromi Kubagawa, and Luan A. Chau
- Subjects
Cancer Research ,Myeloid ,Lymphoma ,Cell Survival ,Cellular differentiation ,Phospholipase C beta ,CELLCYCLE ,Protein tyrosine phosphatase ,Biology ,Malignant transformation ,Proto-Oncogene Proteins c-myc ,Mice ,hemic and lymphatic diseases ,STAT5 Transcription Factor ,medicine ,Animals ,Phosphorylation ,Diacylglycerol kinase ,Myeloproliferative Disorders ,Phospholipase C ,Protein Tyrosine Phosphatase, Non-Receptor Type 6 ,Tumor Suppressor Proteins ,Cell Differentiation ,Cell Biology ,Hematopoietic Stem Cells ,medicine.disease ,Molecular biology ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Oncology ,Mutation ,Cancer research ,Stem cell ,Signal Transduction - Abstract
Given its catalytic activity to generate diacylglycerol and inositol 1,4,5-trisphosphate, phospholipase C (PLC) is implicated in promoting cell growth. However, we found that PLC-beta3-deficient mice develop myeloproliferative disease, lymphoma, and other tumors. The mutant mice have increased numbers of hematopoietic stem cells with increased proliferative, survival, and myeloid-differentiative abilities. These properties are dependent on Stat5 and can be antagonized by the protein phosphatase SHP-1. Stat5-dependent cooperative transformation by active c-Myc and PLC-beta3 deficiency was suggested in mouse lymphomas in PLC-beta3(-/-) and in Emicro-myc;PLC-beta3(+/-) mice and human Burkitt's lymphoma cells. The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-beta3 is likely a tumor suppressor.
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- 2009
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227. FIP1L1-PDGFRα Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells
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Atsushi Iwama, Masahiro Tokunaga, Hirohiko Shibayama, Masato Yasumi, Hirokazu Tanaka, Yuzuru Kanakura, Yusuke Satoh, Itaru Matsumura, Sachiko Ezoe, and Kentaro Fukushima
- Subjects
Receptor, Platelet-Derived Growth Factor alpha ,Oncogene Proteins, Fusion ,Transcription, Genetic ,MAP Kinase Signaling System ,Cellular differentiation ,MAP Kinase Kinase 2 ,MAP Kinase Kinase 1 ,Biology ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Mice ,Molecular Basis of Cell and Developmental Biology ,Megakaryocyte ,Proto-Oncogene Proteins ,Hypereosinophilic Syndrome ,CCAAT-Enhancer-Binding Protein-alpha ,medicine ,Animals ,Humans ,Transplantation, Homologous ,GATA1 Transcription Factor ,Progenitor cell ,Molecular Biology ,Cells, Cultured ,mRNA Cleavage and Polyadenylation Factors ,Hypereosinophilic syndrome ,Hematopoietic Stem Cell Transplantation ,Cell Differentiation ,Cell Biology ,Eosinophil ,Hematopoietic Stem Cells ,medicine.disease ,Cell biology ,Eosinophils ,GATA2 Transcription Factor ,Transplantation ,Haematopoiesis ,Leukemia ,medicine.anatomical_structure ,Chronic Disease ,Trans-Activators ,Cancer research ,Cytokines - Abstract
Although leukemogenic tyrosine kinases (LTKs) activate a common set of downstream molecules, the phenotypes of leukemia caused by LTKs are rather distinct. Here we report the molecular mechanism underlying the development of hypereosinophilic syndrome/chronic eosinophilic leukemia by FIP1L1-PDGFRalpha. When introduced into c-Kit(high)Sca-1(+)Lineage(-) cells, FIP1L1-PDGFRalpha conferred cytokine-independent growth on these cells and enhanced their self-renewal, whereas it did not immortalize common myeloid progenitors in in vitro replating assays and transplantation assays. Importantly, FIP1L1-PDGFRalpha but not TEL-PDGFRbeta enhanced the development of Gr-1(+)IL-5Ralpha(+) eosinophil progenitors from c-Kit(high)Sca-1(+)Lineage(-) cells. FIP1L1-PDGFRalpha also promoted eosinophil development from common myeloid progenitors. Furthermore, when expressed in megakaryocyte/erythrocyte progenitors and common lymphoid progenitors, FIP1L1-PDGFRalpha not only inhibited differentiation toward erythroid cells, megakaryocytes, and B-lymphocytes but aberrantly developed eosinophil progenitors from megakaryocyte/erythrocyte progenitors and common lymphoid progenitors. As for the mechanism of FIP1L1-PDGFRalpha-induced eosinophil development, FIP1L1-PDGFRalpha was found to more intensely activate MEK1/2 and p38(MAPK) than TEL-PDGFRbeta. In addition, a MEK1/2 inhibitor and a p38(MAPK) inhibitor suppressed FIP1L1-PDGFRalpha-promoted eosinophil development. Also, reverse transcription-PCR analysis revealed that FIP1L1-PDGFRalpha augmented the expression of C/EBPalpha, GATA-1, and GATA-2, whereas it hardly affected PU.1 expression. In addition, short hairpin RNAs against C/EBPalpha and GATA-2 and GATA-3KRR, which can act as a dominant-negative form over all GATA members, inhibited FIP1L1-PDGFRalpha-induced eosinophil development. Furthermore, FIP1L1-PDGFRalpha and its downstream Ras inhibited PU.1 activity in luciferase assays. Together, these results indicate that FIP1L1-PDGFRalpha enhances eosinophil development by modifying the expression and activity of lineage-specific transcription factors through Ras/MEK and p38(MAPK) cascades.
- Published
- 2009
228. Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL
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Ichiro Onoyama, Yumiko Gomei, Yuka Nakamura, Yasuhide Hayashi, Sahoko Matsuoka, Atsushi Iwama, Keisuke Ito, Kana Miyamoto, Yoichi Mashimo, Keiko Nakayama, Hiroko Iwasaki, Toshio Suda, Yuichi Oike, Shigeru Chiba, Keiichi I. Nakayama, Yumi Matsuzaki, Akira Hata, Fumio Arai, Hideyuki Oguro, Yasuo Ikeda, Kentaro Hosokawa, Keiyo Takubo, Hiroki Yoshiwara, and Eriko Nitta
- Subjects
F-Box-WD Repeat-Containing Protein 7 ,Ubiquitin-Protein Ligases ,Apoptosis ,Cell Cycle Proteins ,Mice, Transgenic ,Models, Biological ,F-box protein ,Research Communication ,Mice ,Genetics ,medicine ,Humans ,Animals ,Leukemia-Lymphoma, Adult T-Cell ,Cells, Cultured ,Leukemia ,biology ,F-Box Proteins ,Cell Cycle ,Hematopoietic stem cell ,Cell cycle ,Hematopoietic Stem Cells ,medicine.disease ,Haematopoiesis ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Ubiquitin ligase complex ,Mutation ,Perspective ,Cancer research ,biology.protein ,Tumor Suppressor Protein p53 ,Stem cell ,Gene Deletion ,Developmental Biology - Abstract
Common molecular machineries between hematopoietic stem cell (HSC) maintenance and leukemia prevention have been highlighted. The tumor suppressor Fbxw7 (F-box and WD-40 domain protein 7), a subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle. We demonstrate that inactivation of Fbxw7 in hematopoietic cells causes premature depletion of HSCs due to active cell cycling and p53-dependent apoptosis. Interestingly, Fbxw7 deletion also confers a selective advantage to cells with suppressed p53 function, eventually leading to development of T-cell acute lymphoblastic leukemia (T-ALL). Thus, Fbxw7 functions as a fail-safe mechanism against both premature HSC loss and leukemogenesis.
- Published
- 2008
229. Life and death in hematopoietic stem cells
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Hideyuki Oguro and Atsushi Iwama
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Hematopoietic cell ,Immunology ,Polycomb-Group Proteins ,Apoptosis ,hemic and immune systems ,Telomere ,Cell fate determination ,Biology ,Hematopoietic Stem Cells ,Hematopoiesis ,Cell biology ,Repressor Proteins ,Oxidative Stress ,Haematopoiesis ,Animals ,Humans ,Immunology and Allergy ,Cell Lineage ,Stem cell ,Apoptosis Regulatory Proteins ,Cellular Senescence ,Metabolic Networks and Pathways ,Homeostasis - Abstract
Hematopoietic stem cells (HSCs) are defined as primitive cells that are capable of both self-renewal and differentiation into any of the hematopoietic cell lineages. HSC numbers need to be precisely regulated to maintain hematopoietic homeostasis. HSCs undergo several cell fate decisions, including decisions on life and death and self-renewal and differentiation, which have crucial roles in the regulation of their numbers and lifespan. Defects in these processes have been found to contribute to hematopoietic insufficiencies and the development of hematopoietic malignancies. Recent studies have begun to elucidate how HSCs make life and death decisions and the underlying molecular mechanisms involved, highlighting the importance of a balance between survival and death in the regulation of HSCs.
- Published
- 2007
230. Clonal expansion of non-leukemic cells expressing two novel MLL–ELL variants differing in transforming activity
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Satoru Miyagi, Ryuko Cho, Miki Nishimura, Atsushi Iwama, Masahiro Takeuchi, Chiaki Nakaseko, Yasushi Saito, Yusuke Takeda, Chikako Ohwada, and S Ozawa
- Subjects
Genetics ,Cancer Research ,Exon ,Oncology ,Oncogene Proteins ,hemic and lymphatic diseases ,Alternative splicing ,Hematology ,Biology ,neoplasms - Abstract
Clonal expansion of non-leukemic cells expressing two novel MLL – ELL variants differing in transforming activity
- Published
- 2007
231. Enhanced Self-Renewal Capability in Hepatic Stem/Progenitor Cells Drives Cancer Initiation
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Tetsuhiro Chiba, Atsushi Iwama, Yun-Wen Zheng, Kaoru Kita, Yasuni Nakanuma, Masayuki Nakano, Hiromitsu Nakauchi, Yoh Zen, Hideki Taniguchi, Hiromitsu Saisho, Osamu Yokosuka, Hiroyuki Miyoshi, and Masafumi Onodera
- Subjects
Mice, SCID ,Biology ,Mice ,Mice, Inbred NOD ,Cancer stem cell ,Proto-Oncogene Proteins ,medicine ,Animals ,Progenitor cell ,Cells, Cultured ,beta Catenin ,Polycomb Repressive Complex 1 ,Induced stem cells ,Hepatology ,Cell Cycle ,Liver Neoplasms ,Hematopoietic Stem Cell Transplantation ,Gastroenterology ,Nuclear Proteins ,Hematopoietic stem cell ,Hematopoietic Stem Cells ,Molecular biology ,Neural stem cell ,Mice, Inbred C57BL ,Repressor Proteins ,Wnt Proteins ,Endothelial stem cell ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Liver ,Mutation ,Cancer research ,Stem cell ,Signal Transduction ,Adult stem cell - Abstract
Background & Aims: Transformed hematopoietic stem/progenitor cells with an enhanced or acquired self-renewal capability function as leukemic stem cells. In a variety of solid cancers, stem/progenitor cells could be also targets of carcinogenesis. However, it remains unclear whether disruption of stem cell function directly contributes to cancer initiation. We sought to elucidate the mechanisms of self-renewal in hepatic stem/progenitor cells and the relation between stem cell function and hepatocarcinogenesis. Methods: Functional analyses of polycomb-group protein Bmi1 and Wnt/β-catenin, the molecules that are responsible for the self-renewal capability of many types of stem cells, were conducted in c-Kit−CD29+CD49f+/lowCD45−Ter-119− hepatic stem/progenitor cells using retrovirus- or lentivirus-mediated gene transfer. The tumorigenicity of these cells transduced with the indicated retroviruses was also assessed by transplantation into nonobese diabetic/severe combined immunodeficient mice. Results: Forced expression of Bmi1 and constitutively active β-catenin mutant similarly promoted the self-renewal of hepatic stem/progenitor cells. The transplantation of Bmi1- or β-catenin–transduced cells clonally expanded from single hepatic stem/progenitor cells produced tumors, which exhibited the histologic features of combined hepatocellular and cholangiocarcinoma. Conclusions: These observations imply that the dysregulated self-renewal of hepatic stem/progenitor cells serves as an early event in hepatocarcinogenesis, and they highlight the important roles of Bmi1 and the Wnt/β-catenin pathway in regulating the self-renewal of normal or cancer stem cells in liver.
- Published
- 2007
232. Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo
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Atsushi Iwama, Katsuto Hozumi, Mitsuharu Sato, Toshinao Oyama, Hideyuki Oguro, Reiko Sakamoto, Nobuaki Yoshida, Ablimit Muradil, Motoo Kitagawa, Kenji Matsuno, Kenichi Harigaya, and Sonoko Habu
- Subjects
Blotting, Western ,Notch signaling pathway ,Regulator ,Cell Line ,Mice ,Animals ,Lymphocytes ,Lymphopoiesis ,Receptor, Notch1 ,Transcription factor ,Caenorhabditis elegans ,Mice, Knockout ,Genetics ,Multidisciplinary ,biology ,Nuclear Proteins ,Biological Sciences ,Flow Cytometry ,Ligand (biochemistry) ,biology.organism_classification ,Hematopoiesis ,Cell biology ,Notch proteins ,Signal transduction ,Signal Transduction ,Transcription Factors - Abstract
Mastermind (Mam) is one of the elements of Notch signaling, an ancient system that plays a pivotal role in metazoan development. Genetic analyses in Drosophila and Caenorhabditis elegans have shown Mam to be an essential positive regulator of this signaling pathway in these species. Mam proteins bind to and stabilize the DNA-binding complex of the intracellular domains of Notch and CBF-1, Su(H), Lag-1 (CSL) DNA-binding proteins in the nucleus. Mammals have three Mam proteins, which show remarkable similarities in their functions while having an unusual structural diversity. There have also been recent indications that Mam-1 functionally interacts with other transcription factors including p53 tumor suppressor. We herein describe that Mam-1 deficiency in mice abolishes the development of splenic marginal zone B cells, a subset strictly dependent on Notch2, a CSL protein and Delta1 ligand. Mam-1 deficiency also causes a partially impaired development of early thymocytes, while not affecting the generation of definitive hematopoiesis, processes that are dependent on Notch1. We also demonstrate the transcriptional activation of a target promoter by constitutively active forms of Notch to decrease severalfold in cultured Mam-1-deficient cells. These results indicate that Mam-1 is thus required to some extent for Notch-dependent stages in lymphopoiesis, thus supporting the notion that Mam is an essential component of the canonical Notch pathway in mammals.
- Published
- 2007
233. Cytokine Signaling, Lipid Raft Clustering, and HSC Hibernation
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Yohei Morita, Satoshi Yamazaki, Koji Eto, Hiromitsu Nakauchi, Atsushi Iwama, and Hideo Ema
- Subjects
Transcription, Genetic ,Antigens, CD34 ,Biology ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Membrane Microdomains ,History and Philosophy of Science ,Animals ,Humans ,Phosphorylation ,Caenorhabditis elegans ,Lipid raft ,Transcription factor ,Kinase ,General Neuroscience ,Cell Cycle ,Cell cycle ,Hematopoietic Stem Cells ,Lipids ,Cell biology ,Haematopoiesis ,Ki-67 Antigen ,Cytokines ,Stem cell ,Signal transduction ,Intracellular ,Signal Transduction - Abstract
Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche in a noncycling state and enter the cell cycle at long intervals. This unique property of HSCs is reminiscent of hibernation in mammals. However, little is known about inter- and intracellular signaling mechanisms underlying this unique property of HSCs. This is largely due to the paucity of HSCs making application of traditional signal transduction assays difficult. To address these issues, we have developed a novel assay based on in-droplet single-cell staining and quantitative fluorescence imaging analysis. Using this assay system, we demonstrate that freshly isolated HSCs from the BM niche lack lipid raft clustering, exhibit repression of the AKT-FOXO signaling pathway, and express abundant p57(Kip2) cyclin-dependent kinase inhibitor. Lipid raft clustering induced by cytokines was essential for HSC re-entry into the cell cycle. Conversely, inhibition of lipid raft clustering caused sustained nuclear accumulation of FOXO transcription factors and induced HSC hibernation ex vivo. Among niche signals examined, transforming growth factor-beta (TGF-beta) efficiently inhibited lipid raft clustering and induced p57(Kip2) expression, leading to HSC hibernation. These data uncover a critical role for lipid rafts in HSC fate decision and establish the role of TGF-beta as a niche signal in control of HSC hibernation in the BM niche.
- Published
- 2007
234. [Ex vivo expansion of human cord blood hematopoietic stem cells using small-molecule compounds]
- Author
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Atsushi, Iwama
- Subjects
Small Molecule Libraries ,Animals ,Humans ,Fetal Blood ,Hematopoietic Stem Cells ,Cells, Cultured ,Cell Proliferation - Abstract
Recent studies of hematopoietic stem and progenitor cells (HSPCs) have led to the development of new ways to detect and purify HSPCs and have also revealed several intrinsic and extrinsic factors that control the molecular signals fundamental to self-renewal and differentiation of HSPCs. These findings have provided new approaches for expanding HSPCs ex vivo utilizing protein factors and small-molecule compounds (SMCs) and have also demonstrated promising outcomes in clinical trials. Although further technical innovation is still needed, elucidation of the whole picture of signaling pathways critical to HSPCs and manipulation of such pathways by SMCs could establish efficient and robust methods for ex vivo expansion of HSPCs.
- Published
- 2015
235. HISTONE METHYLTRANSFERASE SETDB1 REGULATES ENERGY METABOLISM IN HEMATOPOIETIC STEM AND PROGENITOR CELLS
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Atsushi Iwama, Keiyo Takubo, Hirotaka Matsui, Atsunori Saraya, Shuhei Koide, Hiroshi Kimura, Motohiko Oshima, Toshio Suda, Changshan Wang, Satoru Miyagi, and Yoichi Shinkai
- Subjects
Endothelial stem cell ,Cancer Research ,Haematopoiesis ,Histone methyltransferase ,Genetics ,Energy metabolism ,Cell Biology ,Hematology ,Biology ,Progenitor cell ,Molecular Biology ,Cell biology - Published
- 2015
236. Biological features and biomarkers in hepatocellular carcinoma
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Akinobu Tawada, Atsushi Iwama, Osamu Yokosuka, Sadahisa Ogasawara, Yoshihiko Ooka, Tomoko Saito, Tetsuhiro Chiba, and Eiichiro Suzuki
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Sorafenib ,Hepatology ,business.industry ,Genomic research ,Computational biology ,Review ,Bioinformatics ,medicine.disease_cause ,medicine.disease ,Genome ,digestive system diseases ,Hepatocellular carcinoma ,medicine ,Carcinogenesis ,business ,Gene ,Stem cell biology ,Exome sequencing ,medicine.drug - Abstract
Similar to other cancers, a multistep process of carcinogenesis is observed in hepatocellular carcinoma (HCC). Although the mechanisms underlying the development of HCC have been investigated in terms of oncology, virology, and stem cell biology, the whole picture of hepatocarcinogenesis remains to be elucidated. Recent progress in molecular biology has provided clues to the underlying cause of various diseases. In particular, sequencing technologies, such as whole genome and exome sequencing analyses, have made an impact on genomic research on a variety of cancers including HCC. Comprehensive genomic analyses have detected numerous abnormal genetic alterations, such as mutations and copy number alterations. Based on these findings, signaling pathways and cancer-related genes involved in hepatocarcinogenesis could be analyzed in detail. Simultaneously, a number of novel biomarkers, both from tissue and blood samples, have been recently reported. These biomarkers have been successfully applied to early diagnosis and prognostic prediction of patients with HCC. In this review, we focus on the recent developments in molecular cancer research on HCC and explain the biological features and novel biomarkers.
- Published
- 2015
237. MEK-ERK Activity Regulates the Proliferative Activity of Fetal Hepatoblasts Through Accumulation of p16/19(cdkn2a)
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Akihide Kamiya, Atsushi Iwama, Ayaka Yanagida, Hiromi Chikada, Keiichi Ito, and Hiromitsu Nakauchi
- Subjects
MAPK/ERK pathway ,Liver cytology ,Somatic cell ,MAP Kinase Signaling System ,Mice, Transgenic ,Biology ,Mice ,Fetus ,Animals ,Progenitor cell ,Cells, Cultured ,Cyclin-Dependent Kinase Inhibitor p16 ,Cell Proliferation ,Kinase ,MEK inhibitor ,Mesenchymal stem cell ,Feeder Cells ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,Cell biology ,Transplantation ,Liver ,Hepatocytes ,Developmental Biology - Abstract
Hepatoblasts are somatic progenitor cells in the fetal liver, which retain a high proliferative capacity and differentiate into both hepatocytes and cholangiocytes in vivo. Although efficient expansion of hepatoblasts in vitro has been difficult without genetic modification, we have previously demonstrated that the interaction with mesenchymal cells is important for expansion of hepatoblasts in vitro. In this study, we show cell signaling pathways regulating the long-term proliferative ability of hepatoblasts. Individual primary hepatoblasts derived from mouse fetal livers formed large colonies when cocultured with mesenchymal feeder cells; however, secondary colony formation was unsuccessful, indicating that in vitro culture could induce short-term, but not long-term, proliferation. When the MEK inhibitor, PD0325901, was added to these cultures, hepatoblasts formed large colonies containing many Ki-67-positive cells. Expression of p16/19(cdkn2a), a cyclin-dependent kinase inhibitor, was induced after 3-6 days culture of hepatoblasts, whereas PD0325901 significantly suppressed this expression. Consistent with these observations, fetal hepatoblasts derived from p16/19(cdkn2a) knockout mice showed long-term proliferation without PD0325901, suggesting that MEK activity induced cell cycle arrest through accumulation of p16/19(cdkn2a). In transplantation assays, we could demonstrate that in vitro expanded hepatoblasts could proliferate and differentiate into hepatocytic and cholangiocytic cells in injured livers. It should also be noted that ERK in primary hepatoblasts was not highly activated during fetal liver development. Collectively, all these findings suggest that the MEK/ERK-independent pathway in the fetal liver is involved in hepatoblast proliferation to avoid accumulation of cyclin-dependent kinase inhibitor.
- Published
- 2015
238. The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition
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Makiko Mochizuki-Kashio, Atsushi Iwama, Motohiko Oshima, Changshan Wang, Kazuya Shimoda, Kazumasa Aoyama, Takahisa Tomioka, Akinori Kanai, Goro Sashida, and Hironori Harada
- Subjects
0301 basic medicine ,Methyltransferase ,genetic structures ,Immunology ,Mutation, Missense ,macromolecular substances ,medicine.disease_cause ,Article ,03 medical and health sciences ,Mice ,medicine ,Immunology and Allergy ,Animals ,Enhancer of Zeste Homolog 2 Protein ,Epigenetics ,Research Articles ,Mice, Knockout ,Mutation ,Janus kinase 2 ,biology ,Oncogene ,EZH2 ,HMGA2 Protein ,Polycomb Repressive Complex 2 ,Janus Kinase 2 ,Bromodomain ,Haematopoiesis ,030104 developmental biology ,Amino Acid Substitution ,Primary Myelofibrosis ,Cancer research ,biology.protein ,Neoplastic Stem Cells - Abstract
Loss of Ezh2 in the presence of activating mutation in JAK2 (JAK2V617F) cooperatively alters transcriptional programs of hematopoiesis, activates specific oncogenes, and promotes the development of myelofibrosis., EZH2 is a component of polycomb repressive complex 2 (PRC2) and functions as an H3K27 methyltransferase. Loss-of-function mutations in EZH2 are associated with poorer outcomes in patients with myeloproliferative neoplasms (MPNs), particularly those with primary myelofibrosis (MF [PMF]). To determine how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for an Ezh2 conditional deletion and activating mutation in JAK2 (JAK2V617F) present in patients with PMF. The deletion of Ezh2 in JAK2V617F mice markedly promoted the development of MF, indicating a tumor suppressor function for EZH2 in PMF. The loss of Ezh2 in JAK2V617F hematopoietic cells caused significant reductions in H3K27 trimethylation (H3K27me3) levels, resulting in an epigenetic switch to H3K27 acetylation (H3K27ac). These epigenetic switches were closely associated with the activation of PRC2 target genes including Hmga2, an oncogene implicated in the pathogenesis of PMF. The treatment of JAK2V617F/Ezh2-null mice with a bromodomain inhibitor significantly attenuated H3K27ac levels at the promoter regions of PRC2 targets and down-regulated their expression, leading to the abrogation of MF-initiating cells. Therefore, an EZH2 insufficiency not only cooperated with active JAK2 to induce MF, but also conferred an oncogenic addiction to the H3K27ac modification in MF-initiating cells that was capable of being restored by bromodomain inhibition.
- Published
- 2015
239. [The cancer stem cell model in hematological malignancies]
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Eriko, Nitta and Atsushi, Iwama
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Hematologic Neoplasms ,Neoplastic Stem Cells ,Animals ,Humans ,Cell Separation ,DNA ,Models, Biological ,Epigenesis, Genetic - Abstract
Technological advances such as the high-throughput sequencing are providing us novel aspects and perspectives of cancer stem cells (CSCs). Current evidences support a model where multiple subclones persist, rather than a simple hierarchical model with CSCs. The presence of multiple subclones contributes to increase in fitness and robustness of a cancer, which is reminiscent of the stability in ecosystems. The latest report describing the sequencing of peripheral-blood cells from unselected persons revealed that clonal hematopoiesis with somatic mutations already exists in a fair percentage of elderly persons. The analysis also shed light on some epigenetic modifiers as the driver genes of clonal hematopoiesis. In this article, we review the recent evolution of CSC model in hematology.
- Published
- 2015
240. [Epigenetic dysregulation in myelodysplastic syndrome]
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Goro, Sashida and Atsushi, Iwama
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Epigenomics ,Leukemia, Myeloid, Acute ,Myelodysplastic Syndromes ,Mutation ,Humans ,Epigenesis, Genetic ,Hematopoiesis - Abstract
Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by impaired hematopoiesis and an increased risk of transformation to acute myeloid leukemia. Various epigenetic regulators are mutated in MDS patients, indicating that accumulation of epigenetic alterations together with genetic alterations plays a crucial role in the development of MDS.
- Published
- 2015
241. High Levels of Morphological Variation Despite Close Genetic Relatedness Between Zoanthus aff. vietnamensis and Zoanthus kuroshio (Anthozoa: Hexacorallia)
- Author
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Junzo Tsukahara, Atsushi Iwama, Shunsuke Ono, Tadashi Maruyama, and James Davis Reimer
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Hexacorallia ,Tentacle ,Ecology ,biology ,Molecular Sequence Data ,Zoology ,Anemone ,Biodiversity ,DNA ,Anthozoa ,biology.organism_classification ,Japan ,Species Specificity ,Genus ,RNA, Ribosomal, 16S ,Zoanthus ,DNA, Ribosomal Spacer ,Animals ,Animal Science and Zoology ,Internal transcribed spacer ,Ribosomal DNA ,Phylogeny - Abstract
Recent investigations into the encrusting anemone genus Zoanthus using molecular and morphological techniques have begun to bring order to this taxonomically neglected group. Previous studies have confirmed the existence of three distinct species present in southern Japan: Z. sansibaricus, Z. kuroshio, and Z. gigantus. Results from such studies show species of Zoanthus to be highly morphologically plastic, often incorporating morphotypes with varying oral disk color and oral disk diameter. Literature lists the species Z. aff. vietnamensis as occurring in southern Japan and throughout the western Pacific Ocean, but due to the morphological plasticity of Zoanthus species, a re-examination of Z. aff. vietnamensis using molecular techniques was needed. Here, using mitochondrial 16S rDNA and the nuclear internal transcribed spacer of ribosomal DNA (ITS-rDNA) sequences, as well as morphological data, we have examined several nominal Z. aff. vietnamensis samples collected from Kagoshima Bay and Yakushima Island, Japan. Based on polyp length and diameter, oral disk diameter, mesentery and tentacle numbers, and colony form, Z. aff. vietnamensis is easily distinguishable from Z. sansibaricus, Z. kuroshio, and Z. gigantus. However, despite these clear morphological differences, our mitochondrial and nuclear sequence-based phylogenies indicate that Z. aff. vietnamensis and Z. kuroshio are very closely related (perhaps conspecific), highlighting the morphological plasticity of this genus and the difficulty of species identification based on morphological data alone.
- Published
- 2006
242. Putative 'Stemness' Gene Jam-B Is Not Required for Maintenance of Stem Cell State in Embryonic, Neural, or Hematopoietic Stem Cells
- Author
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Naoki Iwamori, Atsushi Iwama, Hiromitsu Nakauchi, Masami Muramatsu, Satoru Miyagi, Hiroshi Kiyonari, Akihiko Okuda, Yohei Morita, Takehisa Sakaguchi, and Masazumi Nishimoto
- Subjects
Male ,KOSR ,Homeobox protein NANOG ,Heterozygote ,Stem cell theory of aging ,Immunoglobulins ,Embryoid body ,Biology ,Stem cell marker ,Mice ,Neurosphere ,Testis ,Animals ,RNA, Messenger ,Nerve Tissue ,Molecular Biology ,Cells, Cultured ,Crosses, Genetic ,Mice, Knockout ,Multipotent Stem Cells ,Membrane Proteins ,Cell Differentiation ,Articles ,Cell Biology ,Embryo, Mammalian ,Hematopoietic Stem Cells ,Microarray Analysis ,Molecular biology ,humanities ,Cell biology ,Gene Expression Regulation ,Gene Targeting ,Mutation ,Female ,Stem cell ,Cell Adhesion Molecules ,Adult stem cell - Abstract
Many genes have been identified that are specifically expressed in multiple types of stem cells in their undifferentiated state. It is generally assumed that at least some of these putative "stemness" genes are involved in maintaining properties that are common to all stem cells. We compared gene expression profiles between undifferentiated and differentiated embryonic stem cells (ESCs) using DNA microarrays. We identified several genes with much greater signal in undifferentiated ESCs than in their differentiated derivatives, among them the putative stemness gene encoding junctional adhesion molecule B (Jam-B gene). However, in spite of the specific expression in undifferentiated ESCs, Jam-B mutant ESCs had normal morphology and pluripotency. Furthermore, Jam-B homozygous mutant mice are fertile and have no overt developmental defects. Moreover, we found that neural and hematopoietic stem cells recovered from Jam-B mutant mice are not impaired in their ability to self-renew and differentiate. These results demonstrate that Jam-B is dispensable for normal mouse development and stem cell identity in embryonic, neural, and hematopoietic stem cells.
- Published
- 2006
243. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells
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Atsushi Iwama, Satoshi Yamazaki, Koji Eto, Shin-ichiro Takayanagi, Hideo Ema, Hiromitsu Nakauchi, and Yohei Morita
- Subjects
Fluorescent Antibody Technique ,Apoptosis ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Membrane Microdomains ,Animals ,Caenorhabditis elegans ,Molecular Biology ,Lipid raft ,Transcription factor ,Cells, Cultured ,General Immunology and Microbiology ,Kinase ,Stem Cells ,General Neuroscience ,Cell Cycle ,hemic and immune systems ,Cell cycle ,Hematopoietic Stem Cells ,Cell biology ,Mice, Inbred C57BL ,Haematopoiesis ,Cytokines ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,Stem cell ,Intracellular ,Signal Transduction - Abstract
Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche in a noncycling state and enter the cell cycle at long intervals. However, little is known about inter- and intracellular signaling mechanisms underlying this unique property of HSCs. Here, we show that lipid raft clustering is a key event in the regulation of HSC dormancy. Freshly isolated HSCs from the BM niche lack lipid raft clustering, exhibit repression of the AKT-FOXO signaling pathway, and express abundant p57(Kip2) cyclin-dependent kinase inhibitor. Lipid raft clustering induced by cytokines is essential for HSC re-entry into the cell cycle. Conversely, inhibition of lipid raft clustering caused sustained nuclear accumulation of FOXO transcription factors and induced HSC hibernation ex vivo. These data establish a critical role for lipid rafts in regulating the cell cycle, the survival, and the entry into apoptosis of HSCs and uncover a striking similarity in HSC hibernation and Caenorhabditis elegans dauer formation.
- Published
- 2006
244. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties
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Hiromitsu Saisho, Hiromitsu Nakauchi, Atsushi Iwama, Kaoru Kita, Tetsuhiro Chiba, Hideki Taniguchi, Osamu Yokosuka, and Yun-Wen Zheng
- Subjects
Pathology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Transplantation, Heterologous ,Population ,Apoptosis ,In Vitro Techniques ,Biology ,medicine.disease_cause ,Flow cytometry ,Side population ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Humans ,RNA, Neoplasm ,education ,Severe combined immunodeficiency ,education.field_of_study ,Hepatology ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Liver Neoplasms ,Flow Cytometry ,medicine.disease ,Immunohistochemistry ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Cell culture ,Hepatocytes ,Neoplastic Stem Cells ,Keratins ,alpha-Fetoproteins ,Stem cell ,Carcinogenesis ,Neoplasm Transplantation - Abstract
Recent advances in stem cell biology enable us to identify cancer stem cells in solid tumors as well as putative stem cells in normal solid organs. In this study, we applied side population (SP) cell analysis and sorting to established hepatocellular carcinoma (HCC) cell lines to detect subpopulations that function as cancer stem cells and to elucidate their roles in tumorigenesis. Among four cell lines analyzed, SP cells were detected in Huh7 (0.25%) and PLC/PRF/5 cells (0.80%), but not in HepG2 and Huh6 cells. SP cells demonstrated high proliferative potential and anti-apoptotic properties compared with those of non-SP cells. Immunocytochemistry examination showed that SP fractions contain a large number of cells presenting characteristics of both hepatocyte and cholangiocyte lineages. Non-obese diabetic/severe combined immunodeficiency (NOD/SCID) xenograft transplant experiments showed that only 1 x 10(3) SP cells were sufficient for tumor formation, whereas an injection of 1 x 10(6) non-SP cells did not initiate tumors. Re-analysis of SP cell-derived tumors showed that SP cells generated both SP and non-SP cells and tumor-initiating potential was maintained only in SP cells in serial transplantation. Microarray analysis discriminated a differential gene expression profile between SP and non-SP cells, and several so-called "stemness genes" were upregulated in SP cells in HCC cells. In conclusion, we propose that a minority population, detected as SP cells in HCC cells, possess extreme tumorigenic potential and provide heterogeneity to the cancer stem cell system characterized by distinct hierarchy.
- Published
- 2006
245. MOZ is essential for maintenance of hematopoietic stem cells
- Author
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Takahiro Ochiya, Yukiko Aikawa, Atsushi Iwama, Shinobu Ueda, Takuo Katsumoto, Issay Kitabayashi, and Hitoshi Ichikawa
- Subjects
Transcriptional Activation ,Down-Regulation ,Embryonic Development ,Mice ,chemistry.chemical_compound ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Coactivator ,Genetics ,Animals ,Histone acetyltransferase activity ,Cell Lineage ,Erythropoiesis ,Receptors, Cytokine ,Histone Acetyltransferases ,Homeodomain Proteins ,Myelopoiesis ,Oncogene Proteins ,B-Lymphocytes ,Leukemia ,biology ,Gene Expression Regulation, Developmental ,Myeloid leukemia ,Cell Differentiation ,Histone acetyltransferase ,Hematopoietic Stem Cells ,Molecular biology ,Mice, Mutant Strains ,Transplantation ,Proto-Oncogene Proteins c-kit ,Liver ,RUNX1 ,chemistry ,Transcription Coactivator ,Trans-Activators ,biology.protein ,Monocytic leukemia ,Genes, Lethal ,Receptors, Thrombopoietin ,Research Paper ,Developmental Biology - Abstract
Monocytic leukemia zinc-finger protein (MOZ) is a transcriptional coactivator with histone acetyltransferase activity (Champagne et al. 2001; Kitabayashi et al. 2001a). MOZ was first isolated as a gene involved in chromosome translocaton t(8;16) (p11;p13), which is associated with the FAB M4/M5 subtype of acute myeloid leukemia with monocytic arrest (Borrow et al. 1996). This translocation results in the fusion of MOZ to transcription coactivator CBP. MOZ is also fused to CBP-like coactivator p300 and nuclear receptor coactivator TIF2 in leukemia-associated chromosome rearrangements t(8;22) (Chaffanet et al. 2000; Kitabayashi et al. 2001b), and inv(8) (Carapeti et al. 1998; Liang et al. 1998), respectively. In addition, MOZ is involved in the t(2;8) chromosome translocation found in myelodysplastic syndrome (Imamura et al. 2003). In all of the leukemia-associated fusions, MOZ lacks the C-terminal region but retains some of its functional domains, including the histone acetyltransferase domain, PHD-type zinc-finger motif, and histone H1-like domain. MOZ–TIF2 fusion is able to confer properties of leukemic stem cells to committed hematopoietic progenitors, thus inducing acute myeloid leukemia in irradiated recipient mice after transplantation (Deguchi et al. 2003; Huntly et al. 2004). MOZ–CBP inhibits differentiation of M1 myeloid precursor cells into macrophages (Kitabayashi et al. 2001a). It has been reported that MOZ interacts with AML1, and acts as a transcriptional coactivator (Kitabayashi et al. 2001a). AML1 (Runx1) is the most frequent target of chromosome rearrangements associated with acute leukemia. AML1 is essential for generation of hematopoietic stem cells (Okuda et al. 1996; Wang et al. 1996a), and is important for differentiation of megakaryocytes and lymphocytes (Ichikawa et al. 2004; Growney et al. 2005). AML1 forms a stable complex with CBFβ, which is also essential for definitive hematopoiesis (Sasaki et al. 1996; Wang et al. 1996b; Niki et al. 1997). Although MOZ and p300/CBP act as coactivators for AML1, the leukemia-associated MOZ–CBP inhibits AML1-mediated transcription (Kitabayashi et al. 1998, 2001a; Bristow and Shore 2003). The ETS family transcription factor PU.1 (Spi-1) is essential for maintenance of hematopoietic stem cells and development of myeloid and lymphoid lineages (Scott et al. 1994; McKercher et al. 1996; Kim et al. 2004; Iwasaki et al. 2005). Recent studies of mice carrying hypomorphic PU.1 alleles have indicated that reduction in the expression of PU.1 is capable of predisposing mice to AML (Rosenbauer et al. 2004). Zebrafish having a mutation in the MOZ gene exhibit defects in Hox expression and pharyngeal segmental identity (Miller et al. 2004). Mice carrying a mutation in a gene encoding the MOZ-like protein MORF/Querkopf exhibited defects in bone and brain development (Thomas et al. 2000). However, the role of zebrafish MOZ and mouse MORF in hematopoiesis has not been described. In order to clarify the physiological role of MOZ, we generated mutant mice that completely lack expression of MOZ. Involvement in leukemia-associated chromosome rearrangements and interaction with AML1 suggest critical roles of MOZ in hematopoiesis. Thus, we focused on analysis of the hematopoietic system in MOZ-null mice.
- Published
- 2006
246. Morphological and Molecular Revision of Zoanthus (Anthozoa: Hexacorallia) from Southwestern Japan, with Descriptions of Two New Species
- Author
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Shusuke Ono, Atsushi Iwama, Junzo Tsukahara, Kiyotaka Takishita, Tadashi Maruyama, and James Davis Reimer
- Subjects
Hexacorallia ,Molecular Sequence Data ,Zoology ,DNA, Mitochondrial ,DNA, Ribosomal ,Electron Transport Complex IV ,Evolution, Molecular ,Monophyly ,Japan ,Species Specificity ,Genus ,RNA, Ribosomal, 16S ,Anthozoa ,Animals ,Ribosomal DNA ,Phylogeny ,Base Sequence ,biology ,Genetic Variation ,Species diversity ,Sequence Analysis, DNA ,biology.organism_classification ,Zoanthus ,Animal Science and Zoology ,Zoantharia ,Sequence Alignment - Abstract
No clear method of identifying species in the zoanthid genus Zoanthus has been established, due in part to the morphological plasticity of this genus (e.g., in polyp and colony form, oral disk color, tentacle number). Previous research utilizing the mitochondrial cytochrome oxidase I gene (COI) as a phylogenetic marker indicated that Zoanthus spp. in Japan may consist of only one or two species, despite a bewildering variety of observed morphotypes. Here we have utilized not only COI but also mitochondrial 16S ribosomal DNA (mt 16S rDNA) in order to clarify the extent of Zoanthus species diversity in southern Japan. Our molecular genetic results clearly show the presence of three monophyletic Zoanthus species groups with varying levels of morphological plasticity, including the new species Z. gigantus n. sp. and Z. kuroshio n. sp. We describe all three species found in this study, and identify potential morphological characters (coenenchyme and polyp structure as well as polyp external surface pigmentation patterns) useful in Zoanthus species identification. A morphological dichotomous key is provided to assist in field species identification.
- Published
- 2006
247. Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice
- Author
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Atsushi Iwama, Maarten van Lohuizen, Takehiko Kamijo, Hideyuki Oguro, Hiromitsu Nakauchi, and Yohei Morita
- Subjects
Immunology ,macromolecular substances ,Biology ,Mice ,Bone Marrow ,Proto-Oncogene Proteins ,medicine ,Immunology and Allergy ,Animals ,Nuclear protein ,Cyclin-Dependent Kinase Inhibitor p16 ,DNA Primers ,Polycomb Repressive Complex 1 ,Reverse Transcriptase Polymerase Chain Reaction ,Brief Definitive Report ,Hematopoietic stem cell ,Nuclear Proteins ,Cell Biology ,Hematopoietic Stem Cells ,Phenotype ,Neural stem cell ,Mice, Mutant Strains ,Repressor Proteins ,Haematopoiesis ,medicine.anatomical_structure ,BMI1 ,Cancer research ,Brief Definitive Reports ,Bone marrow ,Stem cell - Abstract
The polycomb group (PcG) protein Bmi1 plays an essential role in the self-renewal of hematopoietic and neural stem cells. Derepression of the Ink4a/Arf gene locus has been largely attributed to Bmi1-deficient phenotypes in the nervous system. However, its role in hematopoietic stem cell (HSC) self-renewal remained undetermined. In this study, we show that derepressed p16Ink4a and p19Arf in Bmi1-deficient mice were tightly associated with a loss of self-renewing HSCs. The deletion of both Ink4a and Arf genes substantially restored the self-renewal capacity of Bmi1−/− HSCs. Thus, Bmi1 regulates HSCs by acting as a critical failsafe against the p16Ink4a- and p19Arf-dependent premature loss of HSCs. We further identified a novel role for Bmi1 in the organization of a functional bone marrow (BM) microenvironment. The BM microenvironment in Bmi1−/− mice appeared severely defective in supporting hematopoiesis. The deletion of both Ink4a and Arf genes did not considerably restore the impaired BM microenvironment, leading to a sustained postnatal HSC depletion in Bmi1−/−Ink4a-Arf−/− mice. Our findings unveil a differential role of derepressed Ink4a and Arf on HSCs and their BM microenvironment in Bmi1-deficient mice. Collectively, Bmi1 regulates self-renewing HSCs in both cell-autonomous and nonautonomous manners.
- Published
- 2006
248. Histone acetylation mediated by Brd1 is crucial for Cd8 gene activation during early thymocyte development
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Toshinori Nakayama, Ichiro Taniuchi, Tomoyuki Ishikura, Atsushi Onodera, Makiko Mochizuki-Kashio, Yaeko Nakajima-Takagi, Daniel G. Tenen, Changshan Wang, Shuhei Koide, Atsushi Iwama, Satoru Miyagi, Taku Naito, Haruhiko Koseki, Masamitsu Negishi, Goro Sashida, Atsunori Saraya, Yuta Mishima, Hiroyuki Hosokawa, and Naoto Yamaguchi
- Subjects
CD8 Antigens ,General Physics and Astronomy ,Mice, Transgenic ,Article ,General Biochemistry, Genetics and Molecular Biology ,Epigenesis, Genetic ,Histones ,Mice ,Histone H3 ,Animals ,Epigenetics ,Enhancer ,Histone Acetyltransferases ,Regulation of gene expression ,Thymocytes ,Multidisciplinary ,biology ,Gene Expression Regulation, Developmental ,Acetylation ,Cell Differentiation ,General Chemistry ,Histone acetyltransferase ,Hematopoietic Stem Cells ,Molecular biology ,Immunity, Innate ,Mice, Inbred C57BL ,Thymocyte ,Enhancer Elements, Genetic ,Histone ,biology.protein ,Female ,Protein Processing, Post-Translational ,Signal Transduction - Abstract
During T-cell development, Cd8 expression is controlled via dynamic regulation of its cis-regulatory enhancer elements. Insufficiency of enhancer activity causes variegated Cd8 expression in CD4(+)CD8(+) double-positive (DP) thymocytes. Brd1 is a subunit of the Hbo1 histone acetyltransferase (HAT) complex responsible for acetylation of histone H3 at lysine 14 (H3K14). Here we show that deletion of Brd1 in haematopoietic progenitors causes variegated expression of Cd8, resulting in the appearance of CD4(+)CD8(-)TCRβ(-/low) thymocytes indistinguishable from DP thymocytes in their properties. Biochemical analysis confirms that Brd1 forms a HAT complex with Hbo1 in thymocytes. ChIP analysis demonstrates that Brd1 localizes at the known enhancers in the Cd8 genes and is responsible for acetylation at H3K14. These findings indicate that the Brd1-mediated HAT activity is crucial for efficient activation of Cd8 expression via acetylation at H3K14, which serves as an epigenetic mark that promotes the recruitment of transcription machinery to the Cd8 enhancers.
- Published
- 2014
249. Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation.
- Author
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Kanatsu-Shinohara, Mito, Takuya Yamamoto, Hidehiro Toh, Yasuhiro Kazuki, Kanako Kazuki, Junichi Imoto, Kazuho Ikeo, Motohiko Oshima, Katsuhiko Shirahige, Atsushi Iwama, Yoichi Nabeshima, Hiroyuki Sasaki, and Takashi Shinohara
- Subjects
STEM cells ,REACTIVE oxygen species ,GLYCOLYSIS ,TESTIS ,AGING - Abstract
Because spermatogonial stem cells (SSCs) are immortal by serial transplantation, SSC aging in intact testes is considered to be caused by a deteriorated microenvironment. Here, we report a cell-intrinsic mode of SSC aging by glycolysis activation. Using cultured SSCs, we found that aged SSCs proliferated more actively than young SSCs and showed enhanced glycolytic activity. Moreover, they remained euploid and exhibited stable androgenetic imprinting patterns with robust SSC activity despite having shortened telomeres. Aged SSCs showed increased Wnt7b expression, which was associated with decreased Polycomb complex 2 activity. Our results suggest that aberrant Wnt7b expression activated c-jun N-terminal kinase (JNK), which down-regulated mitochondria numbers by suppressing Ppargc1a. Down-regulation of Ppargc1a probably decreased reactive oxygen species and enhanced glycolysis. Analyses of the Klotho-deficient aging mouse model and 2-yold aged rats confirmed JNK hyperactivation and increased glycolysis. Therefore, not only microenvironment but also intrinsic activation of JNK-mediated glycolysis contributes to SSC aging. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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250. The Hematopoietic Transcription Factor AML1(RUNX1) Is Negatively Regulated by the Cell Cycle ProteinCyclinD3
- Author
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Dong-Er Zhang, Schickwann Tsai, Velvizhi Ranganathan, Luke F. Peterson, Atsushi Iwama, Anita Boyapati, and Daniel G. Tenen
- Subjects
Transcriptional Activation ,Cyclin D ,Cyclin A ,Cyclin B ,Histone Deacetylases ,Cell Line ,Cyclin D1 ,Cyclin-dependent kinase ,Cyclins ,hemic and lymphatic diseases ,Chlorocebus aethiops ,CCAAT-Enhancer-Binding Protein-alpha ,Animals ,Humans ,Cyclin D3 ,neoplasms ,Molecular Biology ,Cyclin-dependent kinase 1 ,biology ,DNA ,Cell Biology ,Hematopoiesis ,Gene Expression Regulation ,Core Binding Factor Alpha 2 Subunit ,biology.protein ,Cancer research ,Cyclin A2 ,Protein Binding ,Signal Transduction - Abstract
The family of cyclin D proteins plays a crucial role in the early events of the mammalian cell cycle. Recent studies have revealed the involvement of AML1 transactivation activity in promoting cell cycle progression through the induction of cyclin D proteins. This information in combination with our previous observation that a region in AML1 between amino acids 213 and 289 is important for its function led us to investigate prospective proteins associating with this region. We identified cyclin D3 by a yeast two-hybrid screen and detected AML1 interaction with the cyclin D family by both in vitro pull-down and in vivo coimmunoprecipitation assays. Furthermore, we demonstrate that cyclin D3 negatively regulates the transactivation activity of AML1 in a dose-dependent manner by competing with CBFbeta for AML1 association, leading to a decreased binding affinity of AML1 for its target DNA sequence. AML1 and its fusion protein AML1-ETO have been shown to shorten and prolong the mammalian cell cycle, respectively. In addition, AML1 promotes myeloid cell differentiation. Thus, our observations suggest that the direct association of cyclin D3 with AML1 functions as a putative feedback mechanism to regulate cell cycle progression and differentiation.
- Published
- 2005
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