Translocation-driven chr19-der(14) interaction is associated with disease-specific transcriptional programs in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is defined by the t(11;14)(q13;q32) translocation, which drives constitutive CCND1 expression, yet the broader regulatory consequences of this rearrangement remain incompletely understood. Here, we combined transcriptomic, epigenomic, Hi-C, and 3D-FISH analyses in primary MCL samples and cell lines to investigate the genome-wide impact of t(11;14) on chromatin organization and gene regulation beyond the rearranged chromosomes. We show that MCL cells exhibit widespread enhancer activation, accompanied by expansion of super-enhancer regions. The translocated CCND1 locus repositions toward the nuclear interior and acquires enhancer-like features. Genome-wide analysis highlighted chromosome 19 as a hotspot of transcriptional upregulation. Notably, Hi-C and 3D-FISH revealed recurrent interchromosomal contacts between chromosome 19 and the CCND1 locus, preferentially involving the derivative chromosome. These contacts colocalize with active RNA polymerase II and are associated with increased expression of nearby chr19 genes, suggesting an association between spatial proximity and transcriptional activation in trans. Minnelide treatment reduced chromatin accessibility at the CCND1 locus, decreased the frequency of chr19-der14 interactions, and partially reversed the MCL transcriptional program, while exerting strong anti-tumor effects in vitro and in vivo. Together, these findings identify a recurrent interchromosomal interaction associated with coordinated gene activation in MCL and suggest that spatial genome reorganization contributes to disease-specific transcriptional programs.