17 results on '"Yuki Kagiyama"'
Search Results
2. Supplemental Methods and Figure Legends from IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia
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Issay Kitabayashi, Kazushi Araki, Takahiko Seki, Hironori Matsunaga, Tomoyoshi Soga, Yuki Kagiyama, Yutaka Shima, Yukiko Aikawa, Takuo Katsumoto, and Yoko Ogawara
- Abstract
Supplemental Methods and Figure Legends
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- 2023
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3. CDKN1C‐mediated growth inhibition by an EZH1/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib
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Koichiro Inaki, Nobuaki Adachi, Suguru Fukuhara, Takuo Katsumoto, Shuhei Fujita, Daisuke Honma, Ayako Kato, Yukio Kobayashi, Kazushi Araki, Yoshimasa Ono, Kazutsune Yamagata, Yutaka Shima, Issay Kitabayashi, Kensei Tobinai, Makoto Nakagawa, and Yuki Kagiyama
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0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,mantle cell lymphoma ,Antineoplastic Agents ,Cyclin-dependent kinase inhibitor 1C ,Lymphoma, Mantle-Cell ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Cyclin D1 ,Cell, Molecular, and Stem Cell Biology ,Piperidines ,immune system diseases ,ibrutinib ,hemic and lymphatic diseases ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Cyclin-Dependent Kinase Inhibitor p57 ,Cell Proliferation ,EZH1/2 ,Chemistry ,Cell growth ,Adenine ,Polycomb Repressive Complex 2 ,General Medicine ,Original Articles ,Cell Cycle Checkpoints ,Cell cycle ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,CDKN1C ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Ibrutinib ,Cancer research ,Mantle cell lymphoma ,Original Article ,Syndecan-1 ,Growth inhibition - Abstract
Mantle cell lymphoma (MCL) is a rare subtype of non‐Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. Here, we examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1/2), OR‐S1 (a close analog of the clinical‐stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib‐resistant MCL patient–derived xenograft (PDX) mouse model, OR‐S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2‐specific inhibitor GSK126, OR‐S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR‐S1–sensitive or insensitive MCL cell lines and showed that OR‐S1 treatment modulated B‐cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1/2 may be a potential novel target for the treatment of aggressive ibrutinib‐resistant MCL via CDKN1C‐mediated cell cycle arrest., This study reveals that oral administration of OR‐S1 significantly suppressed tumor growth in an ibrutinib‐resistant mantle cell lymphoma (MCL) patient–derived xenograft mouse model. OR‐S1 induces cell cycle arrest via the upregulation of CDKN1C. CDKN1C expression was directly regulated by enhancer of zeste homologs 1 and 2 (EZH1/2).
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- 2021
4. NUP98-HBO1-fusion generates phenotypically and genetically relevant chronic myelomonocytic leukemia pathogenesis
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Toshio Kitamura, Jiro Kitaura, Akihiro Ito, Hirotaka Matsui, Hironori Harada, Ye Ding, Norio Komatsu, Naoko Kato, Sayuri Nishikawa, Yoshihiro Hayashi, Yuka Harada, Jun Imagawa, Naoki Shingai, Yuki Kagiyama, Atsushi Iwama, Issay Kitabayashi, Yuki Maemoto, and Shintaro Hokaiwado
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Oncogene Proteins, Fusion ,CD14 ,Chronic myelomonocytic leukemia ,Histones ,Mice ,Monocytosis ,hemic and lymphatic diseases ,medicine ,Histone acetyltransferase activity ,Animals ,Humans ,Progenitor cell ,Histone Acetyltransferases ,Homeodomain Proteins ,Myeloid Neoplasia ,biology ,Hematopoietic stem cell ,Acetylation ,Leukemia, Myelomonocytic, Chronic ,Hematology ,medicine.disease ,Nuclear Pore Complex Proteins ,Leukemia ,Disease Models, Animal ,Histone ,medicine.anatomical_structure ,Phenotype ,biology.protein ,Cancer research ,Disease Progression - Abstract
Chronic myelomonocytic leukemia (CMML) constitutes a hematopoietic stem cell (HSC) disorder characterized by prominent monocytosis and myelodysplasia. Although genome sequencing has revealed the CMML mutation profile, the mechanism of disease development remains unclear. Here we show that aberrant histone acetylation by nucleoporin-98 (NUP98)-HBO1, a newly identified fusion in a patient with CMML, is sufficient to generate clinically relevant CMML pathogenesis. Overexpression of NUP98-HBO1 in murine HSC/progenitors (HSC/Ps) induced diverse CMML phenotypes, such as severe leukocytosis, increased CD115+ Ly6Chigh monocytes (an equivalent subpopulation to human classical CD14+ CD16− monocytes), macrocytic anemia, thrombocytopenia, megakaryocyte-lineage dysplasia, splenomegaly, and cachexia. A NUP98-HBO1–mediated transcriptional signature in human CD34+ cells was specifically activated in HSC/Ps from a CMML patient cohort. Besides critical determinants of monocytic cell fate choice in HSC/Ps, an oncogenic HOXA9 signature was significantly activated by NUP98-HBO1 fusion through aberrant histone acetylation. Increased HOXA9 gene expression level with disease progression was confirmed in our CMML cohort. Genetic disruption of NUP98-HBO1 histone acetyltransferase activity abrogated its leukemogenic potential and disease development in human cells and a mouse model. Furthermore, treatment of azacytidine was effective in our CMML mice. The recapitulation of CMML clinical phenotypes and gene expression profile by the HBO1 fusion suggests our new model as a useful platform for elucidating the central downstream mediators underlying diverse CMML-related mutations and testing multiple compounds, providing novel therapeutic potential.
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- 2018
5. Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD)
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Yuki Kagiyama, Tsuyoshi Fukushima, Kimihito Cojin Kawabata, Noriko Doki, Daichi Inoue, Tomofusa Fukuyama, Tomoyuki Uchida, Makoto Saika, Koutarou Nishimura, Katsuhiro Togami, Naoko Watanabe-Okochi, Toshihiko Oki, Shuhei Asada, Y Hayashi, Takeshi Fujino, Toshio Kitamura, Sayuri Horikawa, Jiro Kitaura, Ryoichi Ono, Yuto Izawa, Tetsuya Nosaka, Susumu Goyama, Fumio Nakahara, Yutaka Enomoto, Yosuke Tanaka, Naoko Kato, Yukiko Komeno, and Reina Nagase
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0301 basic medicine ,Oncogene Proteins, Fusion ,Carcinogenesis ,JB Special Reviews—Cell Fate Decision, and its Underlying Molecular Mechanisms ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Biochemistry ,Translocation, Genetic ,Epigenesis, Genetic ,Mice ,03 medical and health sciences ,medicine ,Animals ,Humans ,Epigenetics ,Molecular Biology ,Gene ,Cell Proliferation ,Genetics ,Acute leukemia ,Mutation ,Myelodysplastic syndromes ,General Medicine ,Hematopoietic Stem Cells ,medicine.disease ,Phenotype ,Leukemia, Myeloid, Acute ,Cell Transformation, Neoplastic ,030104 developmental biology ,Hematologic Neoplasms ,Myelodysplastic Syndromes ,RNA splicing - Abstract
Recent progress in high-speed sequencing technology has revealed that tumors harbor novel mutations in a variety of genes including those for molecules involved in epigenetics and splicing, some of which were not categorized to previously thought malignancy-related genes. However, despite thorough identification of mutations in solid tumors and hematological malignancies, how these mutations induce cell transformation still remains elusive. In addition, each tumor usually contains multiple mutations or sometimes consists of multiple clones, which makes functional analysis difficult. Fifteen years ago, it was proposed that combination of two types of mutations induce acute leukemia; Class I mutations induce cell growth or inhibit apoptosis while class II mutations block differentiation, co-operating in inducing acute leukemia. This notion has been proven using a variety of mouse models, however most of recently found mutations are not typical class I/II mutations. Although some novel mutations have been found to functionally work as class I or II mutation in leukemogenesis, the classical class I/II theory seems to be too simple to explain the whole story. We here overview the molecular basis of hematological malignancies based on clinical and experimental results, and propose a new working hypothesis for leukemogenesis.
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- 2015
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6. Overexpression of RUNX1 short isoform has an important role in the development of myelodysplastic/myeloproliferative neoplasms
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Hironori Harada, Norio Komatsu, Noriko Doki, Kazuteru Ohashi, Hiroko Sakurai, Naoki Shingai, Yosuke Ogata, Yuka Harada, Yuki Kagiyama, and Toshio Kitamura
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0301 basic medicine ,Gene isoform ,Mutation ,CD34 ,Myeloproliferative disease ,Hematology ,Biology ,medicine.disease_cause ,Phenotype ,Stimulus Report ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,RUNX1 ,chemistry ,Cancer research ,medicine - Abstract
Key Points RUNX1a, but not RUNX1b, is overexpressed in CD34+ cells from patients with myelodysplastic/myeloproliferative neoplasms. SRSF2P95H mutation induces RUNX1a overexpression and a monocytic phenotype in TF-1 cells.
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- 2017
7. The molecular basis of myeloid malignancies
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Jiro Kitaura, Katsuhiro Togami, Reina Nagase, Daichi Inoue, Naoko Okochi-Watanabe, Makoto Saika, Tomofusa Fukuyama, Yutaka Enomoto, Noriko Doki, Toshio Kitamura, Kimihito Cojin Kawabata, Tomoyuki Uchida, Fumio Nakahara, Yang Lu, Toshihiko Oki, Naoko Kato, Kumi Izawa, Yuki Kagiyama, Yukiko Komeno, Y Hayashi, and Sayuri Horikawa
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Myeloid ,Cohesin complex ,myeloproliferative neoplasm ,Fusion Proteins, bcr-abl ,General Physics and Astronomy ,epigenetic factors ,Review ,acute myeloid leukemia ,Biology ,medicine.disease_cause ,Epigenesis, Genetic ,splicing ,Mice ,chemistry.chemical_compound ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Myeloproliferative neoplasm ,Cell Proliferation ,Genetics ,Mutation ,Myelodysplastic syndromes ,Myeloid leukemia ,General Medicine ,mutations ,medicine.disease ,myelodysplastic syndromes ,Leukemia, Myeloid, Acute ,Leukemia ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,RUNX1 ,chemistry ,Hematologic Neoplasms ,General Agricultural and Biological Sciences - Abstract
Myeloid malignancies consist of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasm (MPN). The latter two diseases have preleukemic features and frequently evolve to AML. As with solid tumors, multiple mutations are required for leukemogenesis. A decade ago, these gene alterations were subdivided into two categories: class I mutations stimulating cell growth or inhibiting apoptosis; and class II mutations that hamper differentiation of hematopoietic cells. In mouse models, class I mutations such as the Bcr-Abl fusion kinase induce MPN by themselves and some class II mutations such as Runx1 mutations induce MDS. Combinations of class I and class II mutations induce AML in a variety of mouse models. Thus, it was postulated that hematopoietic cells whose differentiation is blocked by class II mutations would autonomously proliferate with class I mutations leading to the development of leukemia. Recent progress in high-speed sequencing has enabled efficient identification of novel mutations in a variety of molecules including epigenetic factors, splicing factors, signaling molecules and proteins in the cohesin complex; most of these are not categorized as either class I or class II mutations. The functional consequences of these mutations are now being extensively investigated. In this article, we will review the molecular basis of hematological malignancies, focusing on mouse models and the interfaces between these models and clinical findings, and revisit the classical class I/II hypothesis.
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- 2014
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8. Low-energy block-level instantaneous comparison 7T SRAM for dual modular redundancy
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Koji Yanagida, Yohei Nakata, Shunsuke Okumura, Hiroshi Kawaguchi, Masahiko Yoshimoto, Yuki Kagiyama, and Shusuke Yoshimoto
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Scheme (programming language) ,business.industry ,Energy consumption ,Condensed Matter Physics ,Electronic, Optical and Magnetic Materials ,Feature (computer vision) ,Cyclic redundancy check ,Block level ,Scalability ,Static random-access memory ,Electrical and Electronic Engineering ,Dual modular redundancy ,business ,computer ,Algorithm ,Computer hardware ,computer.programming_language ,Mathematics - Abstract
This paper proposes a 7T SRAM that realizes a block-level instantaneous comparison feature. The proposed SRAM is useful for operation results comparison in dual modular redundancy (DMR). The data size that can be instantaneously compared is scalable using the proposed structure. The 1-Mb SRAM comprises 16-Kb blocks in which 8-Kb data can be compared in 130.0ns. The proposed scheme reduces energy consumption in data comparison to 1/418, compared to that of a parallel cyclic redundancy check (CRC) circuit.
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- 2012
9. 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
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10. Sphingosine 1-Phosphate Regulates the Egress of IgA Plasmablasts from Peyer’s Patches for Intestinal IgA Responses
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Ikuko Ogahara, Fumi Miura, Morio Higuchi, Hiroshi Kiyono, Jun Kunisawa, Izumi Ishikawa, Yosuke Kurashima, Yuki Kagiyama, and Masashi Gohda
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Immunoglobulin A ,Ovalbumin ,Receptor expression ,Plasma Cells ,Immunology ,Biology ,Plasma cell ,Mice ,Peyer's Patches ,chemistry.chemical_compound ,Intestinal mucosa ,Sphingosine ,medicine ,Animals ,Immunology and Allergy ,Sphingosine-1-phosphate ,Intestinal Mucosa ,B cell ,B-Lymphocytes ,Mice, Inbred BALB C ,Fingolimod Hydrochloride ,Molecular biology ,Intestines ,Lymphatic system ,medicine.anatomical_structure ,chemistry ,Propylene Glycols ,biology.protein ,Female ,Lysophospholipids ,Immunosuppressive Agents - Abstract
It is well established that Peyer’s patches (PPs) are sites for the differentiation of IgA plasma cell precursors, but molecular and cellular mechanisms in their trafficking remain to be elucidated. In this study, we show that alterations in type 1 sphingosine 1-phosphate (S1P) receptor expression during B cell differentiation in the PPs control the emigration of IgA plasma cell precursors. Type 1 S1P receptor expression decreased during the differentiation of IgM+B220+ B cells to IgA+B220+ B cells, but recovered on IgA+B220− plasmablasts for their emigration from the PPs. Thus, IgA+B220− plasmablasts migrated in response to S1P in vitro. Additionally, IgA+ plasmablasts selectively accumulated in lymphatic regions of PPs when S1P-mediated signaling was disrupted by FTY720 treatment. This accumulation of IgA+ plasmablasts in the PPs led to their reduction in the intestinal lamina propria and simultaneous impairment of Ag-specific intestinal IgA production against orally administered Ag. These findings suggest that S1P regulates the retention and emigration of PP B cells and plays key roles in the induction of intestinal IgA production.
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- 2008
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11. IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia
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Tomoyoshi Soga, Yutaka Shima, Takahiko Seki, Yukiko Aikawa, Takuo Katsumoto, Yuki Kagiyama, Kazushi Araki, Yoko Ogawara, Issay Kitabayashi, and Hironori Matsunaga
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Cancer Research ,NPM1 ,Myeloid ,Mutation, Missense ,Biology ,IDH2 ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Progenitor cell ,Myeloid Ecotropic Viral Integration Site 1 Protein ,Homeodomain Proteins ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,Nuclear Proteins ,medicine.disease ,Cell Hypoxia ,Isocitrate Dehydrogenase ,Neoplasm Proteins ,Up-Regulation ,Mice, Inbred C57BL ,Haematopoiesis ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,Cancer research ,Stem cell ,Nucleophosmin ,Neoplasm Transplantation - Abstract
IDH1 and IDH2 mutations occur frequently in acute myeloid leukemia (AML) and other cancers. The mutant isocitrate dehydrogenase (IDH) enzymes convert α-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-KG–dependent dioxygenases. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with nucleophosmin1 (NPM)+/− hematopoietic stem/progenitor cells cotransduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H, and FLT3/ITD), which often occur simultaneously in human AML patients. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q was necessary for the engraftment or survival of NPMc+ cells in vivo. Gene expression analysis indicated that NPMc increased expression of Hoxa9. IDH2/R140Q also increased the level of Meis1 and activated the hypoxia pathway in AML cells. IDH2/R140Q decreased the 5hmC modification and expression of some differentiation-inducing genes (Ebf1 and Spib). Taken together, our results indicated that IDH2 mutation is critical for the development and maintenance of AML stem-like cells, and they provided a preclinical justification for targeting mutant IDH enzymes as a strategy for anticancer therapy. Cancer Res; 75(10); 2005–16. ©2015 AACR.
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- 2014
12. Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells
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Koichi Hattori, Jiro Kitaura, Genta Nagae, Lai Chen-Yi, Tomoyuki Uchida, Yutaka Enomoto, Fumio Nakahara, Toshio Kitamura, Toshihiro Matsukawa, Beate Heissig, Hironori Harada, Makoto Otsu, Kumi Izawa, Yuka Harada, Hiroyuki Aburatani, Toshihiko Oki, Katsuhiro Togami, Chiemi Nishida, Yukiko Komeno, Yuki Kagiyama, Kimihito Cojin Kawabata, and Daichi Inoue
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congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Stromal cell ,Mice, 129 Strain ,Immunology ,Fusion Proteins, bcr-abl ,Kaplan-Meier Estimate ,Biology ,Biochemistry ,Myelogenous ,Mice ,Downregulation and upregulation ,Cell Movement ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Humans ,HES1 ,Bone Marrow Transplantation ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Homeodomain Proteins ,Mice, Knockout ,Models, Genetic ,Cell growth ,Gene Expression Regulation, Leukemic ,Reverse Transcriptase Polymerase Chain Reaction ,NF-kappa B ,Cell Biology ,Hematology ,medicine.disease ,Flow Cytometry ,Up-Regulation ,Mice, Inbred C57BL ,Leukemia ,Matrix Metalloproteinase 9 ,embryonic structures ,Cancer research ,Transcription Factor HES-1 ,Blast Crisis ,Chronic myelogenous leukemia ,Signal Transduction - Abstract
High levels of HES1 expression are frequently found in BCR-ABL(+) chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however, the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-κB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of HES1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, CMPs expressing BCR-ABL and Hes1 secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.
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- 2014
13. Indigenous opportunistic bacteria inhabit mammalian gut-associated lymphoid tissues and share a mucosal antibody-mediated symbiosis
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Tomonori Nochi, Yoshiyuki Goto, Hideki Iijima, Yoshinori Umesaki, Takashi Obata, Yoshiko Fukuyama, Masashi Gohda, Yuki Kagiyama, Shintaro Sato, Yoshikazu Yuki, Hiroshi Kiyono, Hiromi Setoyama, Takahiro Matsuki, Shinichiro Shinzaki, Chihiro Sasakawa, Mitsuo Sakamoto, Naoko Shibata, Yoshimi Benno, Masatoshi Goto, Akira Mukai, Kohtaro Fujihashi, Kazuhiko Nonaka, and Jun Kunisawa
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Lymphoid Tissue ,education ,Molecular Sequence Data ,Spleen ,Antibodies ,Microbiology ,Mice ,Peyer's Patches ,Immune system ,Intestinal mucosa ,RNA, Ribosomal, 16S ,medicine ,Mesenteric lymph nodes ,Animals ,Humans ,Intestinal Mucosa ,health care economics and organizations ,In Situ Hybridization, Fluorescence ,Mice, Inbred BALB C ,Multidisciplinary ,biology ,Bacteria ,Peyer's patch ,Biological Sciences ,biology.organism_classification ,Mice, Inbred C57BL ,Lymphatic system ,medicine.anatomical_structure ,Mice, Inbred DBA ,Immunology ,Lymph Nodes ,Alcaligenes - Abstract
The indigenous bacteria create natural cohabitation niches together with mucosal Abs in the gastrointestinal (GI) tract. Here we report that opportunistic bacteria, largely Alcaligenes species, specifically inhabit host Peyer's patches (PPs) and isolated lymphoid follicles, with the associated preferential induction of antigen-specific mucosal IgA Abs in the GI tract. Alcaligenes were identified as the dominant bacteria on the interior of PPs from naïve, specific-pathogen-free but not from germ-free mice. Oral transfer of intratissue uncultured Alcaligenes into germ-free mice resulted in the presence of Alcaligenes inside the PPs of recipients. This result was further supported by the induction of antigen-specific Ab-producing cells in the mucosal (e.g., PPs) but not systemic compartment (e.g., spleen). The preferential presence of Alcaligenes inside PPs and the associated induction of intestinal secretory IgA Abs were also observed in both monkeys and humans. Localized mucosal Ab-mediated symbiotic immune responses were supported by Alcaligenes -stimulated CD11c + dendritic cells (DCs) producing the Ab-enhancing cytokines TGF-β, B-cell-activating factor belonging to the TNF family, and IL-6 in PPs. These CD11c + DCs did not migrate beyond the draining mesenteric lymph nodes. In the absence of antigen-specific mucosal Abs, the presence of Alcaligenes in PPs was greatly diminished. Thus, indigenous opportunistic bacteria uniquely inhabit PPs, leading to PP-DCs-initiated, local antigen-specific Ab production; this may involve the creation of an optimal symbiotic environment on the interior of the PPs.
- Published
- 2010
14. Critical Roles Of The IDH2 Mutation In Development and Maintenance Of Acute Myeloid Leukemia
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Yoko Ogawara, Takuo Katsumoto, Yukiko Aikawa, Yutaka Shima, Yuki Kagiyama, Hironori Matsunaga, Takahiko Seki, and Issay Kitabayashi
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Mutation ,IDH1 ,Immunology ,Mutant ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Leukemia ,hemic and lymphatic diseases ,Cancer cell ,medicine ,Cancer research ,Stem cell ,Carcinogenesis - Abstract
Mutations in genes encoding isocitrate dehydrogenase (IDH) 1 and 2 are frequently observed in numerous cancers including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and angioimmunoblastic t-cell lymphoma (AITL). The roles of mutant IDHs in tumorigenesis remain unclear because of a lack of appropriate cancer models. Here we established a mouse AML model harboring an IDH2 mutation. IDH1/2 mutations in AML frequently occur simultaneously with mutations in other genes such as NPM, DNMT3A, and FLT3. In accordance with these observations, IDH2/R140Q, NPMc, DNMT3A/R882H and FLT3/ITD cooperatively induced AML in the mouse model. When only three out of the four mutant genes were transduced, the onset of AML was delayed in any combinations. These results clearly indicate that all four mutations are necessary for the efficient induction of AML. Gene-expression analysis indicated that IDH2/R140Q and NPMc cooperatively activate Hoxa9/Meis1 and hypoxia pathways to maintain AML cells in vivo. These two pathways are likely to be important for the IDH2/R140Q-mediated engraftment/survival of NPMc+ cells in mice. DNMT3A/R882H further upregulated the expression levels of Meis1. Furthermore, DNMT3A/R882H promoted the maintenance of cells in an undifferentiated state. Previous studies have shown that FLT3/ITD promotes cell growth and survival. Taken together, our results suggest that multiple signaling pathways are activated in this IDH-mediated AML system. The tumor-associated mutant IDHs catalyze the formation of an oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-ketoglutarate-dependent dioxygenases that includes epigenetic regulators (TETs and KDM4A), hypoxic signaling molecule (EGLN) and others (collagen prolyl 4-hydroxylases). Because mutant IDHs act via a mechanism that is completely different from those of previously described oncogenes, it has attracted increasing attention as a new therapeutic target. Small molecules that potently and selectively inhibit the mutant IDHs induced differentiation of cancer cells in vitro. However, it remains unclear whether the mutant IDHs are valid targets for cancer therapy in vivo. Here we report that AML harboring IDH2/R140Q can be blocked by conditional deletion of IDH2/R140Q, even after leukemia has developed. Deletion of IDH2/R140Q blocked 2-HG production and the maintenance of Csf-1r+ and c-Kit+ leukemia stem cells, resulting in survival of the AML mice. These results indicate that the IDH2 mutation is critical for the development and maintenance of AML stem cells, and that mutant IDHs are promising targets for anticancer therapy. Disclosures: No relevant conflicts of interest to declare.
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- 2013
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15. C-Terminal-Truncating ASXL1 Mutations Induce MDS Via Inhibition Of PRC2
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Hiroyuki Aburatani, Takahiro Ochiya, Daichi Inoue, Koutarou Nishimura, Katsuhiro Togami, Toshihiko Oki, Omar Abdel-Wahab, Kimihito Cojin Kawabata, Toshio Kitamura, Fumio Nakahara, Michael Heuser, Hironori Harada, Hiroshi Kimura, Jiro Kitaura, Yuki Kagiyama, Felicitas Thol, Yutaka Enomoto, Ross L. Levine, and Tomoyuki Uchida
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Myeloid ,Three prime untranslated region ,Immunology ,CLEC5A ,Wild type ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Small hairpin RNA ,Leukemia ,medicine.anatomical_structure ,medicine ,Cancer research ,Myeloproliferative neoplasm - Abstract
Recurrent mutations of ASXL1 (Additional sex combs-like1) are found in various hematological malignancies including myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, and acute myeloid leukemia (AML) with myelodysplasia-related changes. Additionally, ASXL1 mutations are linked with adverse survival in a variety of myeloid malignancies. A previous study demonstrated that loss of ASXL1 in mice promotes myeloid transformation by impairing polycomb repressive complex 2 (PRC2)-mediated gene repression at a number of critical loci and leads to myeloid transformation. However, most ASXL1 mutations are heterozygous and located in the 5’ region of the last exon, indicating a dominant-negative or gain-of-function feature of a truncated ASXL1 protein. Therefore, we investigated if the C-terminal truncated form of ASXL1 (ASXL1-MT) contributes to the development of myeloid malignancies. To this end, we examined the effects of ASXL1-MT using in vitro and in vivo experiments. In in vitro experiment, expression of ASXL1-MT inhibited G-CSF-induced myeloid differentiation of 32Dcl3 cells. In a mouse bone marrow transplantation (BMT) model, ASXL1-MT induced multilineage dysplasia, differentiation block, slowly progressive pancytopenia, BM hyperplasia and splenomegaly. The transduced mice died of severe anemia after a long latency (median survival, 400.5 days), and some of the mice progressed to overt leukemia. Thus, the current model displays all of the features of human MDS. In addition, ASXL1-MT collaborated with N-RAS-G12V, which confers a proliferative advantage, in inducing progression of N-RAS-G12V-induced myeloproliferative neoplasm (MPN) to AML, suggesting that ASXL1-MT contributes to leukemic transformation by inhibiting differentiation of MPN cells. To clarify the molecular mechanism for differentiation block and MDS development induced by ASXL1-MT, we performed expression profiles of 32Dcl3 cells transduced with ASXL1-MT and BM cells of the MDS mice. Of note, gene set enrichment analysis (GSEA) of BM cells of the MDS mice indicated that ASXL1-MT induced an expression profile which inversely correlated with known PRC target genes. In fact, ASXL1-MT remarkably derepressed expression of posterior Hoxa genes, including Hoxa5, Hoxa9 and Hoxa10, which are epigenetically silenced by PRC2 in mature cells. In consistent with this, H3K27me3 was globally reduced in ASXL1-MT transduced cells. We also found ASXL1-MT as well as wild type ASXL1 (ASXL1-WT) can bind to EZH2 and, importantly, co-expression of ASXL1-MT with ASXL1-WT efficiently inhibited the binding between ASXL1-WT and EZH2, suggesting a dominant-negative role of ASXL1-MT against the PRC2 function. Using a chromatin immunoprecipitation (ChIP) assay, we confirmed that H3K27me3 and Ezh2-bindig profoundly decreased around the promoter regions of Hoxa5, Hoxa9, and Hoxa10 in the MDS mice, correlating with the upregulation of their mRNA expression. On the other hand, we found that ASXL1-MT reduced the expression of Clec5a, a type 2 transmembrane receptor and that this reduction was associated with differentiation block of the 32Dcl3 cells. Moreover, utilizing an shRNA or a mutant form of Clec5a, we identified that Clec5a plays essential roles in myeloid differentiation of 32Dcl3 cells. Lastly, we searched for microRNAs deregulated by ASXL1-MT since a large subset of microRNAs are found to be transcriptionally regulated by PRC2. Among upregulated microRNAs related to myeloid malignancies, we found that miR-125a targeted 3’UTR of Clec5a gene, repressed Clec5a expression and inhibited granulocytic differentiation in vitro. Intriguingly, H3K27me3 and Ezh2-bindig greatly decreased around the miR-125a gene in the BM cells of the MDS mice, similar to the results of ChIP assays around Hoxa genes. The present results indicate that ASXL1-MT which results in a truncated protein product may (1) inhibit PRC2-function by impairing the interaction of EZH2 with the ASXL1-WT and (2) promote myeloid transformation through impaired PRC2-mediated repression of posterior HOXAs and miR-125a, and subsequent suppression of CLEC5A. HOXA9 and CLEC5A expression were shown to be high and low, respectively, in MDS patients with ASXL1-MT. Our data provide evidence for a novel axis in MDS pathogenesis and implicate both mutant forms of ASXL1 and miR-125a as therapeutic targets in MDS. Disclosures: No relevant conflicts of interest to declare.
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- 2013
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16. Leukemogenesis induced by c-terminal mutations in the basic leucine zipper domain of C/EBPα
- Author
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Hironori Harada, Noriko Doki, Fumio Nakahara, Katsuhiro Togami, Naoko Kato, Jiro Kitaura, Kotaro Nishimura, Toshio Kitamura, Tomoyuki Uchida, Yuki Kagiyama, Toshihiko Oki, Yuka Harada, and Daichi Inoue
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Cancer Research ,ATF3 ,Terminal (electronics) ,Chemistry ,Genetics ,Basic Leucine Zipper ,Basic helix-loop-helix leucine zipper transcription factors ,bZIP domain ,Cell Biology ,Hematology ,Molecular Biology ,Domain (software engineering) ,Cell biology - Published
- 2013
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17. NPMC cooperates with mutant IDH2 to induce acute myeloid leukemia
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Takuo Katsumoto, Yoko Ogawara, Issay Kitabayashi, Yukiko Aikawa, and Yuki Kagiyama
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Cancer Research ,Mutant ,Genetics ,Cancer research ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,Molecular Biology ,IDH2 - Published
- 2013
- Full Text
- View/download PDF
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