{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T07:52:50Z","timestamp":1793605970174,"version":"4.5.0"},"reference-count":69,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,5,14]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>To elucidate the molecular basis underlying differential responses and resistance to ibrutinib in Waldenstr\u00f6m macroglobulinemia (WM), we conducted a prospective phase 2 trial of ibrutinib monotherapy in treatment-na\u00efve patients. A total of 74 sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multiomics. BM cells were segregated primarily into B-cell\/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B cells\/plasma cells identified 3 distinct evolutionary patterns: evolution (early clone contraction with late clone expansion and increasing genomic complexity), devolution (early clone expansion with late clone contraction and genomic simplification), and no evolution (stable clonal architecture). The evolution pattern was strongly associated with disease progression, whereas devolution correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenstr\u00f6m ibrutinib prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combination strategy. In parallel, GZMB+ CD8+ effector-memory T cells expanded after treatment in patients with progressive disease and coexisted with tumor evolution. These cells exhibited persistently impaired cytotoxic programs (eg, GNLY), a dedifferentiated memory-like state, elevated PDCD1 expression, and reduced T-cell receptor diversity. Together, this study provides, to our knowledge, the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM, introduces the WIP score as a predictive biomarker for treatment response, and identifies actionable tumor-intrinsic and immune mechanisms driving resistance. This trial was registered at www.ClinicalTrials.gov as NCT02604511.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025032268","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T21:26:01Z","timestamp":1770845161000},"page":"2298-2314","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":8,"title":["Evolution of tumor subclones and T-cell dynamics underlie variable ibrutinib responses in Waldenstr\u00f6m macroglobulinemia"],"prefix":"10.1182","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9081-0116","authenticated-orcid":false,"given":"Hao","family":"Sun","sequence":"first","affiliation":[{"name":"1Bing Center for Waldenstr\u00f6m\u2019s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA"},{"name":"2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA"},{"name":"3Department of Medicine, Harvard Medical School, Boston, MA"},{"name":"4State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romanos","family":"Sklavenitis-Pistofidis","sequence":"additional","affiliation":[{"name":"2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA"},{"name":"3Department of Medicine, Harvard Medical School, Boston, MA"},{"name":"5Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3821-9134","authenticated-orcid":false,"given":"Shirong","family":"Liu","sequence":"additional","affiliation":[{"name":"1Bing Center for Waldenstr\u00f6m\u2019s Macroglobulinemia, Dana-Farber Cancer 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