Follicular lymphoma is a slow-growing non-Hodgkin lymphoma that originates from B-cells. In some cancers, including lymphoma, genetic changes can occur. One such change involves a chromosomal translocation, where a segment of one chromosome breaks off and attaches to another. This rearrangement can alter how certain genes function, contributing to disease development.
The Biological Mechanism of Translocation
The hallmark genetic alteration in follicular lymphoma is the t(14;18)(q32;q21) chromosomal translocation. This rearrangement involves an exchange of genetic material between chromosomes 14 and 18. This event occurs during the normal development of B-cells, specifically during V(D)J recombination.
The translocation moves the BCL2 gene from chromosome 18 to a new location next to the immunoglobulin heavy chain (IGH) gene on chromosome 14. The IGH gene is highly active in B-cells, constantly producing components for antibodies. When BCL2 is placed under the regulatory control of the IGH gene’s enhancers, it becomes continuously “switched on,” leading to an overproduction of the BCL2 protein.
Normally, the BCL2 protein functions as an anti-apoptosis factor, meaning it prevents programmed cell death (apoptosis), a natural process that removes old or damaged cells. With the t(14;18) translocation, constant BCL2 overexpression acts like a car with a stuck accelerator pedal. This failure of apoptosis allows abnormal B-cells to accumulate unchecked, forming tumors and contributing to follicular lymphoma progression.
Identifying the Translocation in Patients
Detecting the t(14;18) translocation involves specific laboratory techniques. One widely used method is Fluorescence In Situ Hybridization (FISH). This technique employs fluorescently labeled DNA probes that bind to specific regions on chromosomes 14 and 18.
When probes attach, they “light up” targeted genes, allowing visualization of chromosomes. If the t(14;18) translocation has occurred, distinct fluorescent signals from chromosomes 14 and 18 will appear fused or rearranged. FISH is highly sensitive and specific.
Another sensitive test for identifying the translocation is Polymerase Chain Reaction (PCR). PCR works by amplifying small amounts of DNA, making it possible to identify the unique breakpoint junctions where the two chromosomes have joined.
PCR is effective because the chromosomal breakpoints on chromosome 14 (IGH gene) and chromosome 18 (BCL2 gene) are clustered in specific regions, making them identifiable targets. Both FISH and PCR provide valuable information to confirm the presence of this defining genetic alteration in follicular lymphoma.
Prognostic Impact of the Translocation
The t(14;18) translocation is a defining characteristic found in 80% to 90% of follicular lymphoma cases. While its presence is a strong indicator for diagnosis, it does not by itself dictate a more aggressive disease course in the initial stages. The translocation is considered a “founder event” in lymphoma development, often one of the first genetic changes to occur.
However, the translocation alone is not sufficient to cause the full development of malignant lymphoma. Progression to clinically significant disease involves the accumulation of additional genetic and epigenetic alterations over time. This multi-step process means that while the t(14;18) sets the stage, other changes contribute to the disease’s behavior.
Follicular lymphoma has the potential for “transformation” into a more aggressive form, such as diffuse large B-cell lymphoma. This transformation can occur in 20% to 60% of patients and is associated with a less favorable outlook. Such transformations are driven by the acquisition of further genetic changes rather than solely by the initial t(14;18) translocation.
Influence on Treatment Strategies
Understanding the t(14;18) translocation and its consequence of BCL2 overexpression has directly influenced treatment strategies for follicular lymphoma. Since the constant activation of the BCL2 protein prevents cancer cells from dying, this mechanism becomes a specific target for therapeutic intervention. This approach falls under targeted therapy, which aims to interfere with molecular pathways that drive cancer growth and survival.
A class of drugs, BCL2 inhibitors such as venetoclax, has been developed to counteract this specific survival mechanism. These drugs work by directly binding to the overactive BCL2 protein. By blocking BCL2, these inhibitors allow lymphoma cells to undergo apoptosis.
While BCL2 overexpression is a well-established driver of follicular lymphoma, venetoclax as a single agent has shown varied response rates in clinical trials. This suggests that despite the importance of BCL2, other genetic changes or cellular pathways might also influence a patient’s response to treatment. Therefore, BCL2 inhibitors are explored in combination with other therapies, including traditional chemotherapy or other targeted agents, to improve outcomes.