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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,9,9]]},"abstract":"<jats:p>\n                    Chronic lymphocytic leukemia (CLL) remains incurable despite treatment advances, and a major challenge is that biomarkers that predict response and resistance to current therapies are lacking. We report that activated and proliferating malignant CLL B cells in circulation express PD-1, a protein normally expressed in T cells. PD-1 expression is absent in circulating B cells from healthy controls and nonmalignant B cells from patients with CLL. Circulating PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CLL cells are found in all treatment na\u00efve patients, regardless of immunoglobulin heavy-chain variable region gene mutation status or cytogenetic abnormalities. PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CLL cells are transcriptionally distinct compared to PD-1\n                    <jats:sup>\u2212<\/jats:sup>\n                    CLL cells and upregulate genes associated with cell activation, proliferation, and B cell receptor (BCR) and toll-like receptor (TLR) signaling. Indeed, ex vivo stimulation of the BCR and TLR9 readily increased PD-1 expression in CLL cells from treatment-na\u00efve patients within 24 h, an effect that was blocked by Bruton\u2019s tyrosine kinase inhibitors (BTKi). More importantly, patients initiating BTKi therapy experienced profound reductions in circulating PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CLL cell numbers within 1 mo, which is in line with reduction in Ki-67\n                    <jats:sup>+<\/jats:sup>\n                    CLL cells. Elevated percentages of circulating PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CLL cells also preceded a clinical diagnosis of disease progression in patients receiving BTKi. Thus, our findings indicate that PD-1 expression is a potential biomarker to identify proliferating CLL cells in vivo and will be useful to predict response and resistance to BTKi. In addition, eliminating PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CLL cells with depleting anti-PD-1 monospecific or bispecific antibodies should be explored as a potential therapeutic strategy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2426935122","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T17:57:41Z","timestamp":1757008661000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["PD-1 expression identifies proliferating malignant CLL B cells and is a potential biomarker of response to BTK inhibitor therapy"],"prefix":"10.1073","volume":"122","author":[{"given":"Andres","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine","place":["Atlanta"]},{"name":"Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam N.","family":"Pelletier","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald J.","family":"McGuire","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Tsagiopoulou","sequence":"additional","affiliation":[{"name":"Institute of Applied Biosciences at the Centre for Research and Technology Hellas","place":["Thessaloniki, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Karipidou","sequence":"additional","affiliation":[{"name":"Institute of Applied Biosciences at the Centre for Research and Technology Hellas","place":["Thessaloniki, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Ayers","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa M. K.","family":"Leal","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Churnetski","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin B.","family":"O\u2019Leary","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Switchenko","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory 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