{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T07:37:37Z","timestamp":1789025857743,"version":"build-2803163510"},"reference-count":38,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"4","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO"],"published-print":{"date-parts":[[2024,2,1]]},"abstract":"<jats:sec><jats:title>PURPOSE<\/jats:title><jats:p> A genetic classifier termed LymphGen accurately identifies diffuse large B-cell lymphoma (DLBCL) subtypes vulnerable to Bruton's tyrosine kinase inhibitors (BTKis), but is challenging to implement in the clinic and fails to capture all DLBCLs that benefit from BTKi-based therapy. Here, we developed a novel CD5 gene expression signature as a biomarker of response to BTKi-based therapy in DLBCL. <\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p> CD5 immunohistochemistry (IHC) was performed on 404 DLBCLs to identify CD5 IHC+ and CD5 IHC\u2013 cases, which were subsequently characterized at the molecular level through mutational and transcriptional analyses. A 60-gene CD5 gene expression signature (CD5sig) was constructed using genes differentially expressed between CD5 IHC+ and CD5 IHC\u2013 non\u2013germinal center B-cell-like (non-GCB DLBCL) DLBCLs. This CD5sig was applied to external DLBCL data sets, including pretreatment biopsies from patients enrolled in the PHOENIX study (n = 584) to define the extent to which the CD5sig could identify non-GCB DLBCLs that benefited from the addition of ibrutinib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). <\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p> CD5 expression was observed in 12% of non-GCB DLBCLs. CD5<jats:sup>+<\/jats:sup> DLBCLs displayed transcriptional features of B-cell receptor (BCR) activation and were enriched for BCR-activating mutations known to correlate with BTKi sensitivity. However, most CD5<jats:sup>+<\/jats:sup> DLBCLs lacked canonical BCR-activating mutations or were LymphGen-unclassifiable (LymphGen-Other). The CD5sig recapitulated these findings in multiple independent data sets, indicating its utility in identifying DLBCLs with genetic and nongenetic bases for BCR dependence. Supporting this notion, CD5sig+ DLBCLs derived a selective survival advantage from the addition of ibrutinib to R-CHOP in the PHOENIX study, independent of LymphGen classification. <\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p> CD5sig is a useful biomarker to identify DLBCLs vulnerable to BTKi-based therapies and complements current biomarker approaches by identifying DLBCLs with genetic and nongenetic bases for BTKi sensitivity. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.23.01574","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T21:01:18Z","timestamp":1702328478000},"page":"467-480","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":18,"title":["CD5 Gene Signature Identifies Diffuse Large B-Cell Lymphomas Sensitive to Bruton\u02bcs Tyrosine Kinase Inhibition"],"prefix":"10.1200","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9739-0866","authenticated-orcid":false,"given":"Alan","family":"Cooper","sequence":"first","affiliation":[{"name":"Department of Medicine, Section of Hematology\/Oncology, University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sravya","family":"Tumuluru","sequence":"additional","affiliation":[{"name":"Committee on Cancer Biology, University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Kissick","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girish","family":"Venkataraman","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3497-2513","authenticated-orcid":false,"given":"Joo Y.","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pathology, City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9979-3690","authenticated-orcid":false,"given":"Andrew","family":"Lytle","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerben","family":"Duns","sequence":"additional","affiliation":[{"name":"Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, 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Development, Spring House, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-9425","authenticated-orcid":false,"given":"Srimathi","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Oncology Translational Research, Janssen Research & Development, Lower Gwynedd Township, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonali M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Hematology\/Oncology, University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0435-5947","authenticated-orcid":false,"given":"David W.","family":"Scott","sequence":"additional","affiliation":[{"name":"Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, 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