How Lymphoma Rewires the Human Genome

Lymphomas, a group of blood cancers, often involve chromosomal translocations—errors where segments of chromosomes break and reattach incorrectly. These translocations can significantly disrupt the genome and promote cancer development. Among lymphomas, mantle cell lymphoma is a rare but aggressive subtype that has been closely studied to understand these genetic alterations.

Recent research has shed light on a novel mechanism by which translocations promote cancer progression. Traditionally, scientists focused on the genes directly involved at the points where chromosomes break. However, new findings reveal that translocations can cause widespread genome reprogramming by repositioning powerful regulatory elements known as enhancers.

In mantle cell lymphoma, a translocation between chromosomes 14 and 11 brings the IGH enhancer—an element that boosts antibody gene activity in healthy B cells—adjacent to the CCND1 gene. This enhancer mistakenly treats CCND1 as if it were part of an antibody gene, excessively increasing its activity. While previous studies suggested that overexpression of CCND1 alone was not enough to cause lymphoma, it became clear that the translocation affects many other genes along chromosome 11.

Using advanced CRISPR techniques, scientists replicated the exact translocation in healthy B cells to observe its effects. They discovered that over fifty genes across 50 million base pairs were abnormally active following the chromosomal swap. The three-dimensional structure of DNA inside these cells revealed that the translocation facilitates the enhancer’s intimacy with multiple genes through DNA looping. This spatial reorganization enables the enhancer to activate genes that were previously not targeted, amplifying the cancer’s progression.

Most of these affected genes were already active but were further upregulated by the enhancer’s new position. This nuanced understanding explains why the same genetic alteration can produce different outcomes depending on the cell type and development stage. Moreover, the research proposes that early detection strategies could be developed by profiling epigenetic markers in cells at risk.

This groundbreaking discovery not only broadens the understanding of lymphoma genetics but also opens new paths for targeted therapies. By pinpointing the genes and regulatory elements involved, researchers hope to design interventions that can interfere with this genome rewiring process, offering hope for durable treatments.

Source: medicalxpress.com