{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T08:10:54Z","timestamp":1780387854072,"version":"3.54.1"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Pirtobrutinib (PBN), a non\u2010covalent BTK inhibitor, has been approved by the FDA for relapsed\/refractory mantle cell lymphoma (MCL); however, resistance to PBN has been observed. To dissect the molecular dynamics driving PBN resistance, we performed integrative single\u2010cell multi\u2010omic profiling (scRNA\u2010seq, scATAC\u2010seq, and scDNA\u2010seq) on longitudinal MCL patient samples. Our analyses revealed both genetic and non\u2010genetic routes of resistance: In some patients, resistance involves sequential copy number gains (e.g., 1q, 2p, and 8q) accompanied by transcriptomic reprogramming and epigenetic alterations, whereas in others, resistance occurs through non\u2010genetic mechanisms driven by transcriptional and epigenetic remodeling. Integration of scATAC\u2010seq and scRNA\u2010seq enabled gene regulatory network inference and in silico perturbation analysis, highlighting RAD21 and SMC3, core components of the cohesin complex, as chromatin regulators whose downregulation may re\u2010sensitize cells to PBN. A stem\u2010like malignant B cell population enriched in resistant samples exhibited features of metabolic reprogramming and epithelial\u2010mesenchymal transition. Together, our findings highlight heterogeneous, multi\u2010layered mechanisms of PBN resistance and suggest chromatin regulators as potential therapeutic targets to overcome PBN resistance in MCL.<\/jats:p>","DOI":"10.1002\/ajh.70304","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T04:00:56Z","timestamp":1776484856000},"page":"1632-1649","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dissecting Pirtobrutinib Resistance in Mantle Cell Lymphoma Through Single\u2010Cell Multi\u2010Omics"],"prefix":"10.1002","volume":"101","author":[{"given":"Fangfang","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Lymphoma and Myeloma The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Lymphoma and Myeloma The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng\u2010Huan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Lymphoma and Myeloma The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Lymphoma and Myeloma The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"McIntosh","sequence":"additional","affiliation":[{"name":"Department of Lymphoma and Myeloma The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Lymphoma and Myeloma The University of Texas MD 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Innovation Center Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9748-5486","authenticated-orcid":false,"given":"Michael","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Lymphoma and Myeloma The University of Texas MD Anderson Cancer Center  Houston Texas USA"},{"name":"Department of Stem Cell Transplantation and Cellular Therapy The University of Texas MD Anderson Cancer Center  Houston Texas 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