{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:55:12Z","timestamp":1790517312423,"version":"4.1.0"},"reference-count":52,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,1,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Notch receptors participate in a signaling pathway in which ligand-induced proteolysis frees the Notch intracellular domain (NICD), allowing it to translocate to the nucleus, form a transcription complex, and induce target gene expression. Chronic lymphocytic leukemia\/small lymphocytic lymphoma (CLL\/SLL), splenic marginal zone B-cell lymphoma (SMZL), and distinct subsets of diffuse large B-cell lymphoma (DLBCL) are strongly associated with mutations in the 3\u2032 end of NOTCH1 or NOTCH2 that disrupt a proline, glutamic acid, serine, and threonine (PEST) degron domain and stabilize NICD1 and NICD2. By contrast, mutations leading to constitutive Notch activation are rare in primary B-cell neoplasms, suggesting that Notch activation is confined to ligand-rich tumor microenvironments, or that cryptic strong gain-of-function mutations have been missed in prior analyses. To test these ideas, we used immunohistochemical stains to screen a broad range of B-cell tumors for Notch activation. Our analyses reveal that among small B-cell neoplasms, NICD2 is primarily detected in SMZL and is a common feature of both NOTCH2 wild-type and NOTCH2-mutated SMZLs, similar to prior findings with NOTCH1 in CLL\/SLL. The greatest NOTCH2 activation was observed in NOTCH2-mutated SMZLs, particularly within splenic marginal zones. By contrast, little evidence of NOTCH2 activation was observed in DLBCL, even in NOTCH2-mutated tumors, suggesting that selective pressure for NOTCH2 activation is mainly confined to low-grade B-cell neoplasms, whereas DLBCLs with NOTCH1 mutations frequently showed evidence of ongoing NOTCH1 activation. These observations have important implications for the pathogenic role of Notch and its therapeutic targeting in B-cell lymphomas.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002995","type":"journal-article","created":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T04:07:22Z","timestamp":1610078842000},"page":"71-83","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":25,"title":["Notch activation is pervasive in SMZL and uncommon in DLBCL: implications for Notch signaling in B-cell tumors"],"prefix":"10.1182","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2005-9080","authenticated-orcid":false,"given":"Vignesh","family":"Shanmugam","sequence":"first","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA;"},{"name":"Cancer Program, Broad Institute of MIT and Harvard. Cambridge, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1295-3258","authenticated-orcid":false,"given":"Jeffrey W.","family":"Craig","sequence":"additional","affiliation":[{"name":"Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6413-6586","authenticated-orcid":false,"given":"Laura K.","family":"Hilton","sequence":"additional","affiliation":[{"name":"Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew H.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher K.","family":"Rushton","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kian","family":"Fahimdanesh","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9013-0105","authenticated-orcid":false,"given":"Scott","family":"Lovitch","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Ferland","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, 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