Single Cell RNA Transcriptomics of Mantle Cell Lymphoma Reveals the Presence of Treatment-Resistant Subclones at the Time of Diagnosis.

Mantle cell lymphoma (MCL) is a B-cell malignancy with a chronically relapsing clinical course and pronounced genetic heterogeneity. To investigate the clonal dynamics underlying early disease relapse, we performed single-cell 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-existence of therapy-resistant subclones at diagnosis. Gene set enrichment analysis comparing therapy-resistant and therapy-sensitive clones revealed substantial inter-patient heterogeneity in resistance-associated transcriptional programs. Despite this heterogeneity, convergent dysregulation of cell-cycle control pathways emerged as a shared feature across patients. Furthermore, we investigated a case of SOX11-negative indolent MCL (iMCL) with late relapse characterized by extensive extranodal dissemination, including peripheral blood leukemization and intestinal tumor masses. While bone marrow- and peripheral blood-derived 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-resistant 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.