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Our study shows that patient samples and derived cell lines express CD38 on CTCL cells, and \u03b1CD38 antibodies effectively target CD38 in a mouse model. In vivo \u03b1CD38 antibody treatment led to the loss of CD38 expression in residual tumor cells, highlighting the need for innovative strategies to improve CTCL outcomes despite the CD38 loss in residual tumor cells. To investigate the role of CD38 in CTCL pathology, we used CRISPR-Cas9 to create CD38-deficient (CD38<jats:sup>KO<\/jats:sup>) CTCL cells. These CD38<jats:sup>KO<\/jats:sup> cells showed higher expression of oncogenes <jats:italic>B-catenin<\/jats:italic>, <jats:italic>TCF7<\/jats:italic>, and <jats:italic>BCL6<\/jats:italic>, along with reduced migration. Elevated NAD+ levels in CD38<jats:sup>KO<\/jats:sup> cells increased cellular respiration after CD38 inhibition in CD38<jats:sup>WT<\/jats:sup> cells. In vivo, CD38<jats:sup>KO<\/jats:sup> cell transplants led to more aggressive tumors, likely due to elevated \u03b2-catenin, Bcl6, and Tcf-1 signaling. Prior research in multiple myeloma showed \u03b1CD38 antibody efficacy relies on CD38 expression. We discovered that panobinostat, a histone deacetylase inhibitor, increased surface CD38 expression in CTCL cells dose-dependently. Combining panobinostat with \u03b1CD38 antibody in a CTCL mouse model significantly improved survival compared to the antibody alone, underscoring CD38\u2019s therapeutic potential in CTCL.<\/jats:p>","DOI":"10.1038\/s41375-025-02551-4","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T16:34:07Z","timestamp":1741451647000},"page":"1146-1156","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["CD38 in the pathobiology of cutaneous T-cell lymphoma and the potential for combination therapeutic intervention"],"prefix":"10.1038","volume":"39","author":[{"given":"Colleen","family":"Isabelle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Boles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"McConnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Burzinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Hutchins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Calabretto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Cheslow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin","family":"Chakravarti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierluigi","family":"Porcu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neda","family":"Nikbakht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6269-5424","authenticated-orcid":false,"given":"Anjali","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,8]]},"reference":[{"key":"2551_CR1","doi-asserted-by":"publisher","first-page":"4730","DOI":"10.1200\/JCO.2009.27.7665","volume":"28","author":"NS Agar","year":"2010","unstructured":"Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. 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All animal experiments were conducted with Institutional Animal Care and Use Committee (ID 02234) approval. Studies including human subjects or samples were approved by an Institutional Review Board (IRB 17D.083) and conducted in accordance with the Declaration of Helsinki with informed consent obtained from all subjects.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}