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To investigate the clonal dynamics underlying early disease relapse, we performed single\u2010cell RNA sequencing of paired tumor samples collected at diagnosis and at first relapse. Inference of copy number variants (CNVs) identified multiple subclonal clusters at both time points. In all cases, a minor subclone present at diagnosis harbored a CNV profile highly concordant with that of the dominant relapse clone, indicating the pre\u2010existence of therapy\u2010resistant subclones at diagnosis. Gene set enrichment analysis comparing therapy\u2010resistant and therapy\u2010sensitive clones revealed substantial inter\u2010patient heterogeneity in resistance\u2010associated transcriptional programs. Despite this heterogeneity, convergent dysregulation of cell\u2010cycle control pathways emerged as a shared feature across patients. Furthermore, we investigated a case of SOX11\u2010negative indolent MCL (iMCL) with late relapse characterized by extensive extranodal dissemination, including peripheral blood leukemization and intestinal tumor masses. While bone marrow\u2010 and peripheral blood\u2010derived MCL cells maintained SOX11 negativity and a largely conserved transcriptomic state, intestinal MCL cells displayed blastoid morphology, expression of SOX11, a profoundly remodeled CNV landscape, and the acquisition of multiple additional driver mutations. Collectively, these findings indicate that early relapse in MCL originates from minor therapy\u2010resistant subclones present at diagnosis and subsequently selected under therapeutic pressure. Moreover, disease progression in iMCL may be driven by spatially restricted clonal evolution, with the emergence of aggressive molecular features in distinct anatomical compartments. These results provide mechanistic insight into MCL clonal evolution and relapse biology.<\/jats:p>","DOI":"10.1002\/ajh.70270","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T01:22:16Z","timestamp":1773105736000},"page":"1025-1035","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single Cell\n                    <scp>RNA<\/scp>\n                    Transcriptomics of Mantle Cell Lymphoma Reveals the Presence of Treatment\u2010Resistant Subclones at the Time of Diagnosis"],"prefix":"10.1002","volume":"101","author":[{"given":"Dmitry","family":"Manakov","sequence":"first","affiliation":[{"name":"Institute of Pathological Physiology, First Faculty of Medicine Charles University  Prague Czech 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