Translocations can drive expression changes of multiple genes in regulons covering entire chromosome arms.

Chromosomal translocations have largely been implicated in tumor development. However, beyond the consequences of aberrant gene expression near the breakpoint, their effects remain underexplored. In this work, we characterize the interplay between translocations, chromatin organization and gene expression using mantle cell lymphoma (MCL) as a model. We show by in vitro genomic engineering and in MCL patient samples that translocations can drive transcriptional changes at entire chromosome arms affecting multiple genes in a regulon-like fashion. Moreover, we demonstrate a clear link between the translocation-induced transcriptional alterations and genome organization, with genes most susceptible to change expression forming pre-existing ultra-long-range interactions spanning 50 megabases. The translocation involves the strong immunoglobulin enhancer into this 3D interaction, allowing the spread of its regulatory potential over the entire affected chromosome arm. Finally, we show that translocation-induced effects mainly represent expression enhancement of genes already active prior to translocation formation, highlighting the importance of the epigenetic state of the cell in which this initial hit occurs. In summary, by studying genome organization principles in the context of translocations, we describe a new principle of gene regulation, showing that strong enhancers can induce substantial gene expression enhancement through ultra-long-range interactions affecting entire chromosome arms, representing an important new mechanism in health and disease.