How lymphoma rewires the human genome

Translocations are chromosomal “cut and paste” errors that drive many lymphomas, a type of blood cancer and the sixth most common form of cancer overall. This includes mantle cell lymphoma, a rare but aggressive subtype diagnosed in about one in every 100,000 people each year.

Translocations are known to spark cancer by altering the activity of the genes near the breakpoints where chromosomes snap and rejoin. For example, a translocation can accidentally cut a gene in half, silencing its activity, or create new hybrid proteins that help promote cancer.

A study published in Nucleic Acids Research shows a new way translocations promote cancer. The translocation most typically found in mantle cell lymphoma drags a powerful regulatory element into a new area of the human genome, where its new position allows it to boost the activity of not just one but 50 genes at once.

The discovery of this genome rewiring mechanism shows the traditional focus on the handful of genes at chromosomal breakpoints is too narrow. The study also greatly expands the list of potential drug targets for mantle cell lymphoma, for which there is no known cure.

“We did not expect to see a single translocation boosting the expression of almost 7% of all genes on a single chromosome. The ripples of disruption are much bigger than expected, and also identify new cancer driver genes, each of which represents a new potential therapeutic target,” says Dr. Renée Beekman, corresponding author of the study and researcher at the Center for Genomic Regulation (CRG) in Barcelona.

In mantle cell lymphoma, a piece of chromosome 14 swaps places with a piece of chromosome 11. A gene regulatory element called the IGH enhancer, which normally boosts the activity of antibody production in healthy B cells, lands right beside CCND1, a gene which helps cells divide. The enhancer treats CCND1 as if it were a gene encoding for antibodies, boosting its activity and fueling the disease.

Previous research has shown that boosting CCND1 expression alone is insufficient to kickstart the formation of mantle cell lymphoma. To understand why, the scientists first created translocations in cells in a dish. They used CRISPR to replicate the exact chromosome break seen in patients.

“We built a system to generate translocations in healthy B cells. Because these are engineered cells, we can carry out experiments that are technically or ethically unfeasible with patient tissues, making it a really useful early disease model,” explains Dr. Roser Zaurin, co-author of the study.

The experiments revealed that over fifty genes along the entire chromosome 11 were much more active after the translocation took place. The translocation affected gene activity across 50 million base pairs, a significantly larger space than previously thought.

How DNA folds inside the engineered cells revealed why the translocation affects so many genes at once.

“DNA loops inside cells. It’s what brings two segments of DNA that are far away from each other in two-dimensional space closer together in three-dimensional space. The translocation drags the strong IGH enhancer into a preexisting loop, placing it in a privileged position of control, enabling it to have a widespread impact on dozens of genes at the same time,” explains Dr. Anna Oncins, first author of the study.

Intriguingly, most of the genes affected by the enhancer were not silent to begin with. The IGH enhancer simply dials their activity up. This biological nuance may explain why the same translocation can have different consequences in different cell types or stages of development. Only genes which were already active are boosted.

The findings could lead to new strategies for the early-stage detection of mantle cell lymphomas. “Because the enhancer mainly supercharges genes that were already active in the very first B cell that acquires the swap, epigenetic profiling of at-risk cells could spot dangerous combinations before a mantle cell lymphoma appears,” explains Dr. Beekman.

The authors of the study next plan on studying exactly how the newly identified genes contribute to the initiation and progression of lymphoma.

Understanding and eventually interrupting the effects of the chromosomal translocation could yield broader, more durable therapies for mantle-cell lymphoma and other types of cancers driven by chromosome swaps.