{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:29:51Z","timestamp":1791174591580,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2014,12,1]],"date-time":"2014-12-01T00:00:00Z","timestamp":1417392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Although the role for the individual Notch receptors in early hematopoiesis have been thoroughly investigated in mouse, studies in human have been mostly limited to the use of pan-Notch inhibitors. However, such studies in human are important to predict potential side effects of specific Notch receptor blocking reagents because these are currently being considered as therapeutic tools to treat various Notch-dependent diseases. In this study, we studied the individual roles of Notch1 and Notch3 in early human hematopoietic lineage decisions, particularly during T-lineage specification. Although this process in mice is solely dependent on Notch1 activation, we recently reported Notch3 expression in human uncommitted thymocytes, raising the possibility that Notch3 mediates human T-lineage specification. Although expression of a constitutive activated form of Notch3 (ICN3) results in the induction of T-lineage specification in human CD34+ hematopoietic progenitor cells, similar to ICN1 overexpression, loss-of-function studies using blocking Abs reveal that only Notch1, but not Notch3, is critical in this process. Blocking of Notch1 activation in OP9-DLL4 cocultures resulted in a complete block in T-lineage specification and induced monocytic and plasmacytoid dendritic cell differentiation instead. In fetal thymus organ cultures, impeded Notch1 activation resulted in B and dendritic cell development. In contrast, Notch3 blocking Abs only marginally affected T-lineage specification and hematopoietic differentiation with a slight increase in monocyte development. No induction of B or dendritic cell development was observed. Thus, our results unambiguously reveal a nonredundant role for Notch1 in human T-lineage specification, despite the expression of other Notch receptors.<\/jats:p>","DOI":"10.4049\/jimmunol.1400764","type":"journal-article","created":{"date-parts":[[2014,11,8]],"date-time":"2014-11-08T06:56:36Z","timestamp":1415429796000},"page":"5997-6004","source":"Crossref","is-referenced-by-count":18,"title":["Notch3 Activation Is Sufficient but Not Required for Inducing Human T-Lineage Specification"],"prefix":"10.1093","volume":"193","author":[{"given":"Els","family":"Waegemans","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital , B-9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge","family":"Van de Walle","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital , B-9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelle","family":"De Medts","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital , B-9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda","family":"De Smedt","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital , B-9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"Kerre","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital , B-9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Vandekerckhove","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital , B-9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georges","family":"Leclercq","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital , B-9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical Genetics Research Group and Centre for Molecular Medicine, School of Clinical and Laboratory Sciences, Faculty of Medicine and Human Sciences, University of Manchester , Manchester M13 9PT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Plum","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital , B-9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Taghon","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital , B-9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,12,15]]},"reference":[{"key":"2025030707510763500_r1","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.cell.2009.03.045","article-title":"The canonical Notch signaling pathway: unfolding the activation mechanism","volume":"137","author":"Kopan","year":"2009","journal-title":"Cell"},{"key":"2025030707510763500_r2","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1126\/science.284.5415.770","article-title":"Notch signaling: cell fate control and signal integration in development","volume":"284","author":"Artavanis-Tsakonas","year":"1999","journal-title":"Science"},{"key":"2025030707510763500_r3","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/383707a0","article-title":"Notch3 mutations in CADASIL, a ditary adult-onset condition causing stroke and dementia","volume":"383","author":"Joutel","year":"1996","journal-title":"Nature"},{"key":"2025030707510763500_r4","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1093\/carcin\/bgt127","article-title":"The Notch signaling pathway as a mediator of tumor survival","volume":"34","author":"Capaccione","year":"2013","journal-title":"Carcinogenesis"},{"key":"2025030707510763500_r5","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1126\/science.1102160","article-title":"Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia","volume":"306","author":"Weng","year":"2004","journal-title":"Science"},{"key":"2025030707510763500_r6","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1158\/0008-5472.CAN-04-3132","article-title":"Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers","volume":"65","author":"Haruki","year":"2005","journal-title":"Cancer Res."},{"key":"2025030707510763500_r7","doi-asserted-by":"crossref","first-page":"8051","DOI":"10.1158\/0008-5472.CAN-07-1022","article-title":"Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers","volume":"67","author":"Konishi","year":"2007","journal-title":"Cancer Res."},{"key":"2025030707510763500_r8","doi-asserted-by":"crossref","first-page":"8046","DOI":"10.1074\/jbc.M800170200","article-title":"Modulation of notch signaling by antibodies specific for the extracellular negative regulatory region of Notch3","volume":"283","author":"Li","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2025030707510763500_r9","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1038\/nature08878","article-title":"Therapeutic antibody targeting of individual Notch receptors","volume":"464","author":"Wu","year":"2010","journal-title":"Nature"},{"key":"2025030707510763500_r10","first-page":"1","article-title":"The Notch pathway in hematopoietic stem cells","volume":"360","author":"Bigas","year":"2012","journal-title":"Curr. Top. Microbiol. 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Biol. Ther."},{"key":"2025030707510763500_r15","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1182\/blood-2013-07-505099","article-title":"Notch signals are required for in vitro but not in vivo maintenance of human hematopoietic stem cells and delay the appearance of multipotent progenitors","volume":"123","author":"Benveniste","year":"2014","journal-title":"Blood"},{"key":"2025030707510763500_r16","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.4049\/jimmunol.169.6.3021","article-title":"Active form of Notch imposes T cell fate in human progenitor cells","volume":"169","author":"De Smedt","year":"2002","journal-title":"J. Immunol."},{"key":"2025030707510763500_r17","doi-asserted-by":"crossref","first-page":"3498","DOI":"10.1182\/blood-2005-02-0496","article-title":"Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic\/dendritic-, or T-cell lineage in thymus microenvironment","volume":"106","author":"De Smedt","year":"2005","journal-title":"Blood"},{"key":"2025030707510763500_r18","doi-asserted-by":"crossref","first-page":"4449","DOI":"10.1182\/blood-2010-06-290049","article-title":"Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions","volume":"117","author":"Van de Walle","year":"2011","journal-title":"Blood"},{"key":"2025030707510763500_r19","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1182\/blood-2002-10-3261","article-title":"Sustained Notch1 signaling instructs the earliest human intrathymic precursors to adopt a \u03b3\u03b4T-cell fate in fetal thymus organ culture","volume":"102","author":"Garc\u00eda-Peydr\u00f3","year":"2003","journal-title":"Blood"},{"key":"2025030707510763500_r20","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1182\/blood-2008-07-168906","article-title":"Notch signaling is required for proliferation but not for differentiation at a well-defined \u03b2-selection checkpoint during human T-cell development","volume":"113","author":"Taghon","year":"2009","journal-title":"Blood"},{"key":"2025030707510763500_r21","first-page":"75","article-title":"Notch signaling during human T cell development","volume":"360","author":"Taghon","year":"2012","journal-title":"Curr. 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Signal."},{"key":"2025030707510763500_r31","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1182\/blood.V99.4.1197","article-title":"HOX-A10 regulates hematopoietic lineage commitment: evidence for a monocyte-specific transcription factor","volume":"99","author":"Taghon","year":"2002","journal-title":"Blood"},{"key":"2025030707510763500_r32","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1182\/blood-2007-03-082206","article-title":"Notch signaling induces cytoplasmic CD3\u03b5 expression in human differentiating NK cells","volume":"110","author":"De Smedt","year":"2007","journal-title":"Blood"},{"key":"2025030707510763500_r33","doi-asserted-by":"crossref","first-page":"4468","DOI":"10.4049\/jimmunol.167.8.4468","article-title":"Enforced expression of GATA-3 severely reduces human thymic cellularity","volume":"167","author":"Taghon","year":"2001","journal-title":"J. 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