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  • 1
    Publication Date: 2009-07-22
    Description: Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes, but also with gain-of-function mutations of proto-oncogenes. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases. Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl(-/-) haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to c-Cbl(+/+) HSPCs, and transduction of C-CBL mutants into c-Cbl(-/-) HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl(+/+) background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanada, Masashi -- Suzuki, Takahiro -- Shih, Lee-Yung -- Otsu, Makoto -- Kato, Motohiro -- Yamazaki, Satoshi -- Tamura, Azusa -- Honda, Hiroaki -- Sakata-Yanagimoto, Mamiko -- Kumano, Keiki -- Oda, Hideaki -- Yamagata, Tetsuya -- Takita, Junko -- Gotoh, Noriko -- Nakazaki, Kumi -- Kawamata, Norihiko -- Onodera, Masafumi -- Nobuyoshi, Masaharu -- Hayashi, Yasuhide -- Harada, Hiroshi -- Kurokawa, Mineo -- Chiba, Shigeru -- Mori, Hiraku -- Ozawa, Keiya -- Omine, Mitsuhiro -- Hirai, Hisamaru -- Nakauchi, Hiromitsu -- Koeffler, H Phillip -- Ogawa, Seishi -- 2R01CA026038-30/CA/NCI NIH HHS/ -- England -- Nature. 2009 Aug 13;460(7257):904-8. doi: 10.1038/nature08240. Epub 2009 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genomics Project, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19620960" target="_blank"〉PubMed〈/a〉
    Keywords: Allelic Imbalance ; Amino Acid Sequence ; Animals ; Base Sequence ; Chromosomes, Human, Pair 11/genetics ; Female ; *Genes, Tumor Suppressor ; Humans ; Leukemia, Myeloid/*genetics/metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Mice, Nude ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/genetics/*metabolism ; Mutation ; NIH 3T3 Cells ; Neoplasm Transplantation ; Oncogenes/genetics ; Phosphorylation ; Protein Conformation ; Proto-Oncogene Proteins c-cbl/antagonists & ; inhibitors/chemistry/deficiency/*genetics/*metabolism ; Ubiquitination ; Uniparental Disomy/genetics ; ras Proteins/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2005-09-06
    Description: This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carninci, P -- Kasukawa, T -- Katayama, S -- Gough, J -- Frith, M C -- Maeda, N -- Oyama, R -- Ravasi, T -- Lenhard, B -- Wells, C -- Kodzius, R -- Shimokawa, K -- Bajic, V B -- Brenner, S E -- Batalov, S -- Forrest, A R R -- Zavolan, M -- Davis, M J -- Wilming, L G -- Aidinis, V -- Allen, J E -- Ambesi-Impiombato, A -- Apweiler, R -- Aturaliya, R N -- Bailey, T L -- Bansal, M -- Baxter, L -- Beisel, K W -- Bersano, T -- Bono, H -- Chalk, A M -- Chiu, K P -- Choudhary, V -- Christoffels, A -- Clutterbuck, D R -- Crowe, M L -- Dalla, E -- Dalrymple, B P -- de Bono, B -- Della Gatta, G -- di Bernardo, D -- Down, T -- Engstrom, P -- Fagiolini, M -- Faulkner, G -- Fletcher, C F -- Fukushima, T -- Furuno, M -- Futaki, S -- Gariboldi, M -- Georgii-Hemming, P -- Gingeras, T R -- Gojobori, T -- Green, R E -- Gustincich, S -- Harbers, M -- Hayashi, Y -- Hensch, T K -- Hirokawa, N -- Hill, D -- Huminiecki, L -- Iacono, M -- Ikeo, K -- Iwama, A -- Ishikawa, T -- Jakt, M -- Kanapin, A -- Katoh, M -- Kawasawa, Y -- Kelso, J -- Kitamura, H -- Kitano, H -- Kollias, G -- Krishnan, S P T -- Kruger, A -- Kummerfeld, S K -- Kurochkin, I V -- Lareau, L F -- Lazarevic, D -- Lipovich, L -- Liu, J -- Liuni, S -- McWilliam, S -- Madan Babu, M -- Madera, M -- Marchionni, L -- Matsuda, H -- Matsuzawa, S -- Miki, H -- Mignone, F -- Miyake, S -- Morris, K -- Mottagui-Tabar, S -- Mulder, N -- Nakano, N -- Nakauchi, H -- Ng, P -- Nilsson, R -- Nishiguchi, S -- Nishikawa, S -- Nori, F -- Ohara, O -- Okazaki, Y -- Orlando, V -- Pang, K C -- Pavan, W J -- Pavesi, G -- Pesole, G -- Petrovsky, N -- Piazza, S -- Reed, J -- Reid, J F -- Ring, B Z -- Ringwald, M -- Rost, B -- Ruan, Y -- Salzberg, S L -- Sandelin, A -- Schneider, C -- Schonbach, C -- Sekiguchi, K -- Semple, C A M -- Seno, S -- Sessa, L -- Sheng, Y -- Shibata, Y -- Shimada, H -- Shimada, K -- Silva, D -- Sinclair, B -- Sperling, S -- Stupka, E -- Sugiura, K -- Sultana, R -- Takenaka, Y -- Taki, K -- Tammoja, K -- Tan, S L -- Tang, S -- Taylor, M S -- Tegner, J -- Teichmann, S A -- Ueda, H R -- van Nimwegen, E -- Verardo, R -- Wei, C L -- Yagi, K -- Yamanishi, H -- Zabarovsky, E -- Zhu, S -- Zimmer, A -- Hide, W -- Bult, C -- Grimmond, S M -- Teasdale, R D -- Liu, E T -- Brusic, V -- Quackenbush, J -- Wahlestedt, C -- Mattick, J S -- Hume, D A -- Kai, C -- Sasaki, D -- Tomaru, Y -- Fukuda, S -- Kanamori-Katayama, M -- Suzuki, M -- Aoki, J -- Arakawa, T -- Iida, J -- Imamura, K -- Itoh, M -- Kato, T -- Kawaji, H -- Kawagashira, N -- Kawashima, T -- Kojima, M -- Kondo, S -- Konno, H -- Nakano, K -- Ninomiya, N -- Nishio, T -- Okada, M -- Plessy, C -- Shibata, K -- Shiraki, T -- Suzuki, S -- Tagami, M -- Waki, K -- Watahiki, A -- Okamura-Oho, Y -- Suzuki, H -- Kawai, J -- Hayashizaki, Y -- FANTOM Consortium -- RIKEN Genome Exploration Research Group and Genome Science Group (Genome Network Project Core Group) -- TGM03P17/Telethon/Italy -- TGM06S01/Telethon/Italy -- New York, N.Y. -- Science. 2005 Sep 2;309(5740):1559-63.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16141072" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Animals ; Base Sequence ; Conserved Sequence ; DNA, Complementary/chemistry ; *Genome ; Genome, Human ; Genomics ; Humans ; Mice/*genetics ; Promoter Regions, Genetic ; Proteins/genetics ; RNA/chemistry/classification ; RNA Splicing ; RNA, Untranslated/chemistry ; Regulatory Sequences, Ribonucleic Acid ; *Terminator Regions, Genetic ; *Transcription Initiation Site ; *Transcription, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2011-09-13
    Description: Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent ( approximately 45 to approximately 85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoshida, Kenichi -- Sanada, Masashi -- Shiraishi, Yuichi -- Nowak, Daniel -- Nagata, Yasunobu -- Yamamoto, Ryo -- Sato, Yusuke -- Sato-Otsubo, Aiko -- Kon, Ayana -- Nagasaki, Masao -- Chalkidis, George -- Suzuki, Yutaka -- Shiosaka, Masashi -- Kawahata, Ryoichiro -- Yamaguchi, Tomoyuki -- Otsu, Makoto -- Obara, Naoshi -- Sakata-Yanagimoto, Mamiko -- Ishiyama, Ken -- Mori, Hiraku -- Nolte, Florian -- Hofmann, Wolf-Karsten -- Miyawaki, Shuichi -- Sugano, Sumio -- Haferlach, Claudia -- Koeffler, H Phillip -- Shih, Lee-Yung -- Haferlach, Torsten -- Chiba, Shigeru -- Nakauchi, Hiromitsu -- Miyano, Satoru -- Ogawa, Seishi -- R01 CA026038/CA/NCI NIH HHS/ -- England -- Nature. 2011 Sep 11;478(7367):64-9. doi: 10.1038/nature10496.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21909114" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/genetics ; Exome/genetics ; Hematopoiesis/genetics ; Humans ; Mutation/*genetics ; Myelodysplastic Syndromes/*genetics ; Nuclear Proteins/genetics ; Polymorphism, Single Nucleotide/genetics ; RNA Splice Sites/genetics ; RNA Splicing/*genetics ; Ribonucleoproteins/genetics ; Spliceosomes/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 1996-07-12
    Description: Hematopoietic stem cells (HSCs) supply all blood cells throughout life by making use of their self-renewal and multilineage differentiation capabilities. A monoclonal antibody raised to the mouse homolog of CD34 (mCD34) was used to purify mouse HSCs to near homogeneity. Unlike in humans, primitive adult mouse bone marrow HSCs were detected in the mCD34 low to negative fraction. Injection of a single mCD34(lo/-), c-Kit+, Sca-1(+), lineage markers negative (Lin-) cell resulted in long-term reconstitution of the lymphohematopoietic system in 21 percent of recipients. Thus, the purified HSC population should enable analysis of the self-renewal and multilineage differentiation of individual HSCs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Osawa, M -- Hanada, K -- Hamada, H -- Nakauchi, H -- New York, N.Y. -- Science. 1996 Jul 12;273(5272):242-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba Science-City, Ibaraki 305, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8662508" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD34/*analysis ; Base Sequence ; *Bone Marrow Cells ; Cell Differentiation ; Cell Lineage ; Cell Separation ; DNA Primers ; *Hematopoiesis ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*cytology/immunology ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Time Factors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 1994-04-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakamura, Y -- Nakauchi, H -- New York, N.Y. -- Science. 1994 Apr 22;264(5158):588-9.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8160019" target="_blank"〉PubMed〈/a〉
    Keywords: *Apoptosis ; Base Sequence ; Cell Division ; Cell Line ; Erythropoietin/pharmacology ; Hematopoietic Stem Cells/cytology/*metabolism ; Humans ; Molecular Sequence Data ; Receptors, Erythropoietin/chemistry/genetics/*physiology ; Signal Transduction ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 1994-02-25
    Description: CD8 is either an alpha alpha homodimer or an alpha beta heterodimer, although most peripheral CD8-lineage T cells express only the CD8 alpha beta heterodimer. The physiological function of CD8 beta was elucidated with mice that were chimeric for the homozygous disruption of the CD8 beta gene. The CD8 beta-1- T cells developed normally to CD4+CD8+ stage, but did not efficiently differentiate further, which resulted in few peripheral CD8+ T cells. The number of peripheral CD8+ T cells was restored by transfer of an exogenous CD8 beta gene into CD8 beta-deficient T cells. Thus, CD8 beta is necessary for the maturation of CD8+ T cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakayama, K -- Negishi, I -- Kuida, K -- Louie, M C -- Kanagawa, O -- Nakauchi, H -- Loh, D Y -- AI 34580/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 1994 Feb 25;263(5150):1131-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8108731" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD4/genetics ; Antigens, CD8/chemistry/genetics/*physiology ; CD4-CD8 Ratio ; Cell Differentiation ; Cell Line ; Chimera ; Histocompatibility Antigens Class I/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; Phenotype ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocyte Subsets/cytology/*immunology/metabolism ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 1992-08-21
    Description: A form of the human erythropoietin receptor (EPOR) was identified in which the cytoplasmic region is truncated by alternative splicing. The truncated form of the receptor (EPOR-T) is the most prevalent form of EPOR in early-stage erythroid progenitor cells, but the full-length EPOR (EPOR-F) becomes the most prevalent form in late-stage progenitors. EPOR-T can transduce a mitogenic signal. However, cells transfected with EPOR-T are more prone to programmed cell death than those expressing EPOR-F. EPOR-F may transduce a signal to prevent programmed cell death that is independent of the mitogenic signal, and alternative splicing of the EPOR gene may have an important role in erythropoiesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakamura, Y -- Komatsu, N -- Nakauchi, H -- New York, N.Y. -- Science. 1992 Aug 21;257(5073):1138-41.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cell Growth and Differentiation, Tsukuba Life Science Center, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1324524" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Sequence ; DNA/chemistry/genetics ; Erythrocyte Aging/*physiology ; Erythroid Precursor Cells/metabolism ; Genetic Vectors ; Humans ; Molecular Sequence Data ; Polymerase Chain Reaction ; RNA Splicing ; RNA, Messenger/genetics ; Receptors, Cell Surface/chemistry/genetics/*physiology ; Receptors, Erythropoietin ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2015-11-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sharma, Arun -- Sebastiano, Vittorio -- Scott, Christopher T -- Magnus, David -- Koyano-Nakagawa, Naoko -- Garry, Daniel J -- Witte, Owen N -- Nakauchi, Hiromitsu -- Wu, Joseph C -- Weissman, Irving L -- Wu, Sean M -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):640. doi: 10.1126/science.350.6261.640-a. Epub 2015 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA. ; Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA. Stem Cell Institute and Paul and Sheila Wellstone Muscular Dystrophy Center, University of Minnesota, Minneapolis, MN 55455, USA. Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. ; Broad Stem Cell Research Center and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. ; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Center for Stem Cell Biology and Regenerative Medicine, The University of Tokyo, Tokyo, Japan. ; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. irv@stanford.edu smwu@stanford.edu. ; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. irv@stanford.edu smwu@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542560" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Bioethical Issues ; Blastocyst ; *Chimera ; Financial Management/ethics ; Humans ; Mice ; National Institutes of Health (U.S.)/economics/ethics ; Pluripotent Stem Cells/*transplantation ; Stem Cell Research/economics/*ethics ; United States
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2016-02-13
    Description: Haematopoietic stem cells (HSCs) are arguably the most extensively characterized tissue stem cells. Since the identification of HSCs by prospective isolation, complex multi-parameter flow cytometric isolation of phenotypic subsets has facilitated studies on many aspects of HSC biology, including self-renewal, differentiation, ageing, niche, and diversity. Here we demonstrate by unbiased multi-step screening, identification of a single gene, homeobox B5 (Hoxb5, also known as Hox-2.1), with expression in the bone marrow that is limited to long-term (LT)-HSCs in mice. Using a mouse single-colour tri-mCherry reporter driven by endogenous Hoxb5 regulation, we show that only the Hoxb5(+) HSCs exhibit long-term reconstitution capacity after transplantation in primary transplant recipients and, notably, in secondary recipients. Only 7-35% of various previously defined immunophenotypic HSCs are LT-HSCs. Finally, by in situ imaging of mouse bone marrow, we show that 〉94% of LT-HSCs (Hoxb5(+)) are directly attached to VE-cadherin(+) cells, implicating the perivascular space as a near-homogenous location of LT-HSCs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, James Y -- Miyanishi, Masanori -- Wang, Sean K -- Yamazaki, Satoshi -- Sinha, Rahul -- Kao, Kevin S -- Seita, Jun -- Sahoo, Debashis -- Nakauchi, Hiromitsu -- Weissman, Irving L -- F30-HL122096/HL/NHLBI NIH HHS/ -- R01 CA086065/CA/NCI NIH HHS/ -- R01 HL058770/HL/NHLBI NIH HHS/ -- T32 GM007365/GM/NIGMS NIH HHS/ -- U01 HL099999/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):223-7. doi: 10.1038/nature16943.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. ; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. ; Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863982" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/metabolism ; Biomarkers/analysis ; Bone Marrow/metabolism ; Cadherins/metabolism ; Cell Self Renewal ; Gene Expression Regulation ; Genes, Reporter/genetics ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*cytology/*metabolism ; Homeodomain Proteins/genetics/*metabolism ; Immunophenotyping ; Male ; Mice ; Mice, Inbred C57BL ; *Stem Cell Niche
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Biochemical and Biophysical Research Communications 186 (1992), S. 342-347 
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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