{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:02:45Z","timestamp":1791198165024,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2009,10,8]],"date-time":"2009-10-08T00:00:00Z","timestamp":1254960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"NIH","award":["5P01 DK53074"],"award-info":[{"award-number":["5P01 DK53074"]}]},{"name":"NIH","award":["R01 CA086065"],"award-info":[{"award-number":["R01 CA086065"]}]},{"name":"NIH","award":["R01 DK43726"],"award-info":[{"award-number":["R01 DK43726"]}]},{"name":"National Health & Medical Research Council CJ Martin Fellowship"},{"name":"and Japanese Society of Promotion of Science Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hematopoietic stem cells (HSCs) are rare, ancestral cells that underlie the development, homeostasis, aging, and regeneration of the blood. Here we show that the chromatin-associated protein Ikaros is a crucial self-renewal regulator of the long-term (LT) reconstituting subset of HSCs. Ikaros, and associated family member proteins, are highly expressed in self-renewing populations of stem cells. Ikaros point mutant mice initially develop LT-HSCs with the surface phenotype cKit+Thy1.1(lo)Lin(-\/lo)Sca1+Flk2-CD150+ during fetal ontogeny but are unable to maintain this pool, rapidly losing it within two days of embryonic development. A synchronous loss of megakaryocyte\/erythrocyte progenitors results, along with a fatal, fetal anemia. At this time, mutation of Ikaros exerts a differentiation defect upon common lymphoid progenitors that cannot be rescued with an ectopic Notch signal in vitro, with hematopoietic cells preferentially committing to the NK lineage. Althoughdispensable for the initial embryonic development of blood, Ikaros is clearly needed for maintenance of this tissue. Achieving successful clinical tissue regeneration necessitates understanding degeneration, and these data provide a striking example by a discrete genetic lesion in the cells underpinning tissue integrity during a pivotal timeframe of organogenesis.<\/jats:p><jats:p>Disclosure of potential conflicts of interest is found at the end of this article.<\/jats:p>","DOI":"10.1002\/stem.232","type":"journal-article","created":{"date-parts":[[2009,10,8]],"date-time":"2009-10-08T16:03:33Z","timestamp":1255017813000},"page":"3082-3092","source":"Crossref","is-referenced-by-count":25,"title":["Self-Renewal of the Long-Term Reconstituting Subset of Hematopoietic Stem Cells Is Regulated by Ikaros"],"prefix":"10.1093","volume":"27","author":[{"given":"Peter","family":"Papathanasiou","sequence":"first","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA"},{"name":"Present Address: Australian Phenomics Facility, Australian National University, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne L.","family":"Attema","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Karsunky","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA"},{"name":"Present Address: Cellerant Therapeutics, San Carlos, California 94070, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Hosen","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA"},{"name":"Present Address: Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yovina","family":"Sontani","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard F.","family":"Hoyne","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Tunningley","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen T.","family":"Smale","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Molecular Biology Institute, and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irving L.","family":"Weissman","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, and Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,10,8]]},"reference":[{"key":"2022011223172636300_bib1","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nature07038","article-title":"Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal","volume":"453","author":"Zon","year":"2008","journal-title":"Nature"},{"key":"2022011223172636300_bib2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/35102167","article-title":"Stem cells, cancer, and cancer stem cells","volume":"414","author":"Reya","year":"2001","journal-title":"Nature"},{"key":"2022011223172636300_bib3","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/nrc1592","article-title":"Leukaemia stem cells and the evolution of cancer-stem-cell research","volume":"5","author":"Huntly","year":"2005","journal-title":"Nat Rev Cancer"},{"key":"2022011223172636300_bib4","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.cell.2006.03.011","article-title":"Stem cells and cancer: Two faces of eve","volume":"124","author":"Clarke","year":"2006","journal-title":"Cell"},{"key":"2022011223172636300_bib5","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1126\/science.1106114","article-title":"Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells","volume":"307","author":"Opferman","year":"2005","journal-title":"Science"},{"key":"2022011223172636300_bib6","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.cell.2007.01.003","article-title":"FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress","volume":"128","author":"Tothova","year":"2007","journal-title":"Cell"},{"key":"2022011223172636300_bib7","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1146\/annurev.genet.39.110304.095817","article-title":"Connecting mammalian genome with phenome by ENU mouse mutagenesis: gene combinations specifying the immune system","volume":"39","author":"Papathanasiou","year":"2005","journal-title":"Annu Rev Genet"},{"key":"2022011223172636300_bib8","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/nrg2431","article-title":"Trends in large-scale mouse mutagenesis: From genetics to functional genomics","volume":"9","author":"Gondo","year":"2008","journal-title":"Nat Rev Genet"},{"key":"2022011223172636300_bib9","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nature05875","article-title":"DNA repair is limiting for haematopoietic stem cells during aging","volume":"447","author":"Nijnik","year":"2007","journal-title":"Nature"},{"key":"2022011223172636300_bib10","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0092-8674(94)90407-3","article-title":"The Ikaros gene is required for the development of all lymphoid lineages","volume":"79","author":"Georgopoulos","year":"1994","journal-title":"Cell"},{"key":"2022011223172636300_bib11","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S1074-7613(03)00168-7","article-title":"Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor","volume":"19","author":"Papathanasiou","year":"2003","journal-title":"Immunity"},{"key":"2022011223172636300_bib12","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1073\/pnas.95.2.657","article-title":"Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes","volume":"95","author":"Klug","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011223172636300_bib13","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/ni1314","article-title":"Early hematopoietic lineage restrictions directed by Ikaros","volume":"7","author":"Yoshida","year":"2006","journal-title":"Nat Immunol"},{"key":"2022011223172636300_bib14","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1084\/jem.190.9.1201","article-title":"Defects in hematopoietic stem cell activity in Ikaros mutant mice","volume":"190","author":"Nichogiannopoulou","year":"1999","journal-title":"J Exp Med"},{"key":"2022011223172636300_bib15","doi-asserted-by":"crossref","first-page":"10302","DOI":"10.1073\/pnas.92.22.10302","article-title":"The purification and characterization of fetal liver hematopoietic stem cells","volume":"92","author":"Morrison","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011223172636300_bib16","first-page":"293","article-title":"Relative to adult marrow, fetal liver repopulates nearly five times more efficiently long-term than short-term","volume":"25","author":"Harrison","year":"1997","journal-title":"Exp Hematol"},{"key":"2022011223172636300_bib17","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/0092-8674(90)90262-D","article-title":"A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells","volume":"62","author":"Ikuta","year":"1990","journal-title":"Cell"},{"key":"2022011223172636300_bib18","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S1074-7613(00)80371-4","article-title":"Developing lymph nodes collect CD4+CD3- LT\u03b2+ cells that can differentiate to APC, Nk Cells, And Follicular cells But Not T Or B cells","volume":"7","author":"Mebius","year":"1997","journal-title":"Immunity"},{"key":"2022011223172636300_bib19","doi-asserted-by":"crossref","first-page":"5878","DOI":"10.1073\/pnas.0700460104","article-title":"Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties","volume":"104","author":"Bowie","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011223172636300_bib20","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.cell.2005.05.026","article-title":"SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells","volume":"121","author":"Kiel","year":"2005","journal-title":"Cell"},{"key":"2022011223172636300_bib21","doi-asserted-by":"crossref","first-page":"e28","DOI":"10.1371\/journal.pgen.0010028","article-title":"Differential expression of novel potential regulators in hematopoietic stem cells","volume":"1","author":"Forsberg","year":"2005","journal-title":"PLoS Genetics"},{"key":"2022011223172636300_bib22","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1126\/science.2898810","article-title":"Purification and characterization of mouse hematopoietic stem cells","volume":"241","author":"Spangrude","year":"1988","journal-title":"Science"},{"key":"2022011223172636300_bib23","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1126\/science.273.5272.242","article-title":"Long-term lymphohematopoietic reconstitution by a single CD34-low\/negative hematopoietic stem cell","volume":"273","author":"Osawa","year":"1996","journal-title":"Science"},{"key":"2022011223172636300_bib24","doi-asserted-by":"crossref","first-page":"14541","DOI":"10.1073\/pnas.261562798","article-title":"Flk-2 is a marker in hematopoietic stem cell differentiation: A simple method to isolate long-term stem cells","volume":"98","author":"Christensen","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011223172636300_bib25","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/S1074-7613(01)00220-5","article-title":"Upregulation of Flt3 expression within the bone marrow Lin-Sca1+c-kit+ stem cell compartment is accompanied by loss of self-renewal capacity","volume":"15","author":"Adolfsson","year":"2001","journal-title":"Immunity"},{"key":"2022011223172636300_bib26","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1101\/gad.12.6.782","article-title":"Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin","volume":"12","author":"Hahm","year":"1998","journal-title":"Genes Dev"},{"key":"2022011223172636300_bib27","doi-asserted-by":"crossref","first-page":"38347","DOI":"10.1074\/jbc.M005457200","article-title":"Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities","volume":"275","author":"Perdomo","year":"2000","journal-title":"J Biol Chem"},{"key":"2022011223172636300_bib28","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1093\/emboj\/16.8.2004","article-title":"Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation","volume":"16","author":"Morgan","year":"1997","journal-title":"EMBO J"},{"key":"2022011223172636300_bib29","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1111\/j.1365-2141.2008.07065.x","article-title":"Ikaros regulates human haemoglobin switching by facilitating developmental stage specific interactions between the individual globin gene promoters and a chromatin hub","volume":"141","author":"Keys","year":"2008","journal-title":"Br J Haematol"},{"key":"2022011223172636300_bib30","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/S0092-8674(00)80165-8","article-title":"Definitive hematopoiesis is autonomously initiated by the AGM region","volume":"86","author":"Medvinsky","year":"1996","journal-title":"Cell"},{"key":"2022011223172636300_bib31","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/ni1560","article-title":"Of lineage and legacy: The development of mammalian hematopoietic stem cells","volume":"9","author":"Dzierzak","year":"2008","journal-title":"Nat Immunol"},{"key":"2022011223172636300_bib32","article-title":"Evaluation of the long-term reconstituting subset of hematopoietic stem cells with CD150","author":"Papathanasiou","year":"2009","journal-title":"Stem Cells"},{"key":"2022011223172636300_bib33","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S1535-6108(03)00137-5","article-title":"Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in NotchIC-induced T cell leukemogenesis","volume":"3","author":"Beverly","year":"2003","journal-title":"Cancer Cell"},{"key":"2022011223172636300_bib34","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1038\/81390","article-title":"Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalised by constitutive Notch1 signaling","volume":"6","author":"Varnum-Finney","year":"2000","journal-title":"Nat Med"},{"key":"2022011223172636300_bib35","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/S1074-7613(02)00474-0","article-title":"Induction of T cell development from hematopoietic progenitor cells in vitro","volume":"17","author":"Schmitt","year":"2002","journal-title":"Immunity"},{"key":"2022011223172636300_bib36","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1084\/jem.186.2.173","article-title":"Identification of a novel developmental stage marking lineage commitment of progenitor thymocytes","volume":"186","author":"Carlyle","year":"1997","journal-title":"J Exp Med"},{"key":"2022011223172636300_bib37","doi-asserted-by":"crossref","first-page":"6557","DOI":"10.1128\/MCB.00729-06","article-title":"Putative \u201cstemness\u201d gene Jam-B is not required for maintenance of stem cell state in embryonic, neural, or hematopoetic stem cells","volume":"26","author":"Sakaguchi","year":"2006","journal-title":"Mol Cell Biol"},{"key":"2022011223172636300_bib38","doi-asserted-by":"crossref","first-page":"14290","DOI":"10.1073\/pnas.0502132102","article-title":"Diversification of stem cell molecular repertoire by alternative splicing","volume":"102","author":"Pritsker","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011223172636300_bib39","doi-asserted-by":"crossref","first-page":"9194","DOI":"10.1073\/pnas.0503280102","article-title":"Cell intrinsic alterations underlie hematopoietic stem cell aging","volume":"102","author":"Rossi","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011223172636300_bib40","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nature01587","article-title":"Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells","volume":"423","author":"Park","year":"2003","journal-title":"Nature"},{"key":"2022011223172636300_bib41","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1634\/stemcells.2006-0229","article-title":"Bmi-1-green fluorescent protein-knock-in mice reveal the dynamic regulation of bmi-1 expression in normal and leukemic hematopoietic cells","volume":"25","author":"Hosen","year":"2007","journal-title":"Stem Cells"},{"key":"2022011223172636300_bib42","doi-asserted-by":"crossref","first-page":"7465","DOI":"10.1128\/MCB.00715-08","article-title":"Ikaros represses the transcriptional response to Notch signaling in T-cell development","volume":"28","author":"Kleinmann","year":"2008","journal-title":"Mol Cell Biol"},{"key":"2022011223172636300_bib43","doi-asserted-by":"crossref","first-page":"6265","DOI":"10.4049\/jimmunol.181.9.6265","article-title":"Ikaros regulates Notch target gene expression in developing thymocytes","volume":"181","author":"Chari","year":"2008","journal-title":"J Immunol"},{"key":"2022011223172636300_bib44","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.immuni.2007.02.010","article-title":"Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits","volume":"26","author":"Thompson","year":"2007","journal-title":"Immunity"},{"key":"2022011223172636300_bib45","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nrm1938","article-title":"Chromatin in pluripotent embryonic stem cells and differentiation","volume":"7","author":"Meshorer","year":"2006","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2022011223172636300_bib46","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1101\/gad.11.6.774","article-title":"Multilineage gene expression precedes commitment in the hemopoietic system","volume":"11","author":"Hu","year":"1997","journal-title":"Genes Dev"},{"key":"2022011223172636300_bib47","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S1534-5807(02)00201-0","article-title":"Myeloid or lymphoid promiscuity as a critical step in hematopoietic lineage commitment","volume":"3","author":"Miyamoto","year":"2002","journal-title":"Dev Cell"},{"key":"2022011223172636300_bib48","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.immuni.2009.01.014","article-title":"Genome-wide lineage-specific transcriptional networks underscore Ikaros-dependent lymphoid priming in hematopoietic stem cells","volume":"30","author":"Ng","year":"2009","journal-title":"Immunity"},{"key":"2022011223172636300_bib49","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.molcel.2004.12.028","article-title":"Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1","volume":"17","author":"Vakoc","year":"2005","journal-title":"Mol Cell"},{"key":"2022011223172636300_bib50","doi-asserted-by":"crossref","first-page":"12371","DOI":"10.1073\/pnas.0704468104","article-title":"Epigenetic characterization of hematopoietic stem cell differentiation using miniChIP and bisulfite sequencing analysis","volume":"104","author":"Attema","year":"2007","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.232","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/stem.232","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/stem.232","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/27\/12\/3082\/41949821\/stmcls_27_12_3082.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/27\/12\/3082\/41949821\/stmcls_27_12_3082.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,17]],"date-time":"2024-03-17T00:12:12Z","timestamp":1710634332000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/27\/12\/3082-3092\/6402019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,10,8]]},"references-count":50,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2009,10,8]]},"published-print":{"date-parts":[[2009,12,1]]}},"URL":"https:\/\/doi.org\/10.1002\/stem.232","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2009,12,1]]},"published":{"date-parts":[[2009,10,8]]}}}