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The present study aimed to investigate the biological impact of this mutation in MCL and its potential as a therapeutic target.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Activation of Notch1 signaling upon ligand-stimulation and inhibitory effects of the monoclonal anti-Notch1 antibody OMP-52M51 in\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -mutated and -unmutated MCL cells were assessed by Western Blot and gene expression profiling. Effects of OMP-52M51 treatment on tumor cell migration and tumor angiogenesis were evaluated with chemotaxis and HUVEC tube formation assays. The expression of\n                      <jats:italic>Delta-like ligand 4<\/jats:italic>\n                      (DLL4) in MCL lymph nodes was analyzed by immunofluorescence staining and confocal microscopy. A MCL mouse model was used to assess the activity of OMP-52M51 in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Notch1 expression can be effectively stimulated in\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -mutated Mino cells by DLL4, whereas in the\n                      <jats:italic>NOTCH1-<\/jats:italic>\n                      unmutated cell line JeKo-1, less effect was observed upon any ligand-stimulation. DLL4 was expressed by histiocytes in both,\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -mutated and \u2013unmutated MCL lymph nodes. Treatment of\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -mutated MCL cells with the monoclonal anti-Notch1 antibody OMP-52M51 effectively prevented DLL4-dependent activation of Notch1 and suppressed the induction of numerous direct Notch target genes involved in lymphoid biology, lymphomagenesis and disease progression. Importantly, in lymph nodes from primary MCL cases with\n                      <jats:italic>NOTCH1\/2<\/jats:italic>\n                      mutations, we detected an upregulation of the same gene sets as observed in DLL4-stimulated Mino cells. Furthermore, DLL4 stimulation of\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -mutated Mino cells enhanced tumor cell migration and angiogenesis, which could be abolished by treatment with OMP-52M51. Importantly, the effects observed were specific for\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -mutated cells as they did not occur in the\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -wt cell line JeKo-1. Finally, we confirmed the potential activity of OMP-52M51 to inhibit DLL4-induced Notch1-Signaling in vivo in a xenograft mouse model of MCL.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      DLL4 effectively stimulates Notch1 signaling in\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -mutated MCL and is expressed by the microenvironment in MCL lymph nodes. Our results indicate that specific inhibition of the Notch1-ligand-receptor interaction might provide a therapeutic alternative for a subset of MCL patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-019-1458-7","type":"journal-article","created":{"date-parts":[[2019,11,1]],"date-time":"2019-11-01T09:03:26Z","timestamp":1572599006000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy"],"prefix":"10.1186","volume":"38","author":[{"given":"Elisabeth","family":"Silkenstedt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Arenas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berta","family":"Colom-Sanmart\u00ed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00edlvia","family":"Xargay-Torrent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morihiro","family":"Higashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariadna","family":"Gir\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanina","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Fuentes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter E.","family":"Aulitzky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"van der Kuip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00edlvia","family":"Be\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L.","family":"Toribio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Campo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f2nica","family":"L\u00f3pez-Guerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7486-8484","authenticated-orcid":false,"given":"Dolors","family":"Colomer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,1]]},"reference":[{"issue":"Suppl 3","key":"1458_CR1","doi-asserted-by":"publisher","first-page":"iii83","DOI":"10.1093\/annonc\/mdu264","volume":"25","author":"M Dreyling","year":"2014","unstructured":"Dreyling M, Geisler C, Hermine O, et al. 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The ethical approval for this project including informed patient consent was granted following guidelines of the Hospital Cl\u00ednic Ethics Committee.Procedures involving animals and their care are conforming to institutional guidelines that comply with national and international laws and policies (EEC Council Directive 86\/609, OJ L 358, 12 December, 1987) and were authorized by the local ethical committee.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"446"}}