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dc.contributor.authorKluk, Michael J.en_US
dc.contributor.authorAshworth, Todden_US
dc.contributor.authorWang, Hongfangen_US
dc.contributor.authorKnoechel, Birgiten_US
dc.contributor.authorMason, Emily F.en_US
dc.contributor.authorMorgan, Elizabeth A.en_US
dc.contributor.authorDorfman, Daviden_US
dc.contributor.authorPinkus, Geraldineen_US
dc.contributor.authorWeigert, Oliveren_US
dc.contributor.authorHornick, Jason L.en_US
dc.contributor.authorChirieac, Lucian R.en_US
dc.contributor.authorHirsch, Michelleen_US
dc.contributor.authorOh, David J.en_US
dc.contributor.authorSouth, Andrew P.en_US
dc.contributor.authorLeigh, Irene M.en_US
dc.contributor.authorPourreyron, Celineen_US
dc.contributor.authorCassidy, Andrew J.en_US
dc.contributor.authorDeAngelo, Daniel J.en_US
dc.contributor.authorWeinstock, David M.en_US
dc.contributor.authorKrop, Ian E.en_US
dc.contributor.authorDillon, Deborahen_US
dc.contributor.authorBrock, Jane E.en_US
dc.contributor.authorLazar, Alexander J. F.en_US
dc.contributor.authorPeto, Myronen_US
dc.contributor.authorCho, Raymond J.en_US
dc.contributor.authorStoeck, Alexanderen_US
dc.contributor.authorHaines, Brian B.en_US
dc.contributor.authorSathayanrayanan, Sriramen_US
dc.contributor.authorRodig, Scotten_US
dc.contributor.authorAster, Jon C.en_US
dc.date.accessioned2014-02-18T18:11:53Z
dc.date.issued2013en_US
dc.identifier.citationKluk, M. J., T. Ashworth, H. Wang, B. Knoechel, E. F. Mason, E. A. Morgan, D. Dorfman, et al. 2013. “Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry.” PLoS ONE 8 (6): e67306. doi:10.1371/journal.pone.0067306. http://dx.doi.org/10.1371/journal.pone.0067306.en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11717646
dc.description.abstractFixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pone.0067306en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688991/pdf/en
dash.licenseLAAen_US
dc.titleGauging NOTCH1 Activation in Cancer Using Immunohistochemistryen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS ONEen
dash.depositing.authorKluk, Michael J.en_US
dc.date.available2014-02-18T18:11:53Z
dc.identifier.doi10.1371/journal.pone.0067306*
dash.authorsorderedfalse
dash.contributor.affiliatedAshworth, Todd
dash.contributor.affiliatedMorgan, Elizabeth
dash.contributor.affiliatedDorfman, David
dash.contributor.affiliatedMason, Emily F.
dash.contributor.affiliatedKluk, Michael J.
dash.contributor.affiliatedWang, Hongfang
dash.contributor.affiliatedBrock, Jane
dash.contributor.affiliatedPinkus, Geraldine
dash.contributor.affiliatedAster, Jon
dash.contributor.affiliatedRodig, Scott
dash.contributor.affiliatedHornick, Jason
dash.contributor.affiliatedHirsch, Michelle
dash.contributor.affiliatedDillon, Deborah
dash.contributor.affiliatedChirieac, Lucian


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