Strategy combining targeted therapies is effective in B-cell lymphomas such as mantle cell lymphoma (MCL), but acquired resistances remain a recurrent issue. Herein, we performed integrative longitudinal genomic and single-cell RNA-seq analyses of MCL patients treated with targeted therapies against CD20, BCL2 and BTK (i.e., OAsIs trial). We revealed the emergence of subclones with a selective advantage against OAsIs combination in vivo and showed that resistant cells were characterized …