Genes serve as fundamental instructions that guide the development and operation of all living organisms. These instructions are typically organized in a precise order within our DNA, dictating the production of specific proteins that perform various functions within cells. However, sometimes these genetic instructions can become abnormally combined, leading to what are known as gene fusions. These fusions hold importance in both biological understanding and medical applications.
Understanding Gene Fusions
A gene fusion occurs when two previously distinct genes, or parts of them, join together to form a single, new hybrid gene. This genetic rearrangement results in a continuous sequence of DNA that can then be transcribed and translated as one unit. This process creates a novel protein, often called a fusion protein. This fusion protein combines segments from original proteins, resulting in a structure and function different from either parent.
This hybrid gene leads to the production of a protein the cell would not normally make. This new protein’s properties are a blend of its original components, but its activity can be entirely new or significantly altered. Understanding these new protein products is central to grasping the biological impact of gene fusions.
How Gene Fusions Arise
Gene fusions primarily arise from errors during DNA repair processes or as a result of chromosomal rearrangements. One common mechanism is a chromosomal translocation, where a piece of one chromosome breaks off and attaches to a different chromosome. If this breakage and rejoining happen within or between two genes, it can fuse them together. For example, the Philadelphia chromosome, found in chronic myeloid leukemia, is a classic translocation where parts of chromosomes 9 and 22 swap, creating the BCR-ABL1 fusion gene.
Another mechanism involves chromosomal inversions, where a segment of a chromosome breaks off, flips around, and reattaches in reverse orientation. If the breakpoints of such an inversion occur within two different genes, they can become fused when the segment reinserts. Deletions can also lead to fusions when genetic material between two genes is lost, bringing the formerly separated genes into close proximity and allowing them to join.
Consequences of Gene Fusions
The significance of gene fusions stems from the altered or novel functions of the resulting fusion proteins. A fusion protein might combine the regulatory region of one gene with the coding sequence of another, leading to the unregulated production of a protein that is normally tightly controlled. For instance, a growth-promoting protein could be continuously active, driving abnormal cell proliferation. This altered activity often disrupts normal cellular signaling pathways.
Such disruptions can manifest as enhanced enzymatic activity, altered protein-protein interactions, or changes in subcellular localization. The fusion protein might gain new binding partners or lose existing ones, thereby changing its role within the cell. These molecular changes contribute to dysfunctional cellular processes, such as uncontrolled cell division or resistance to programmed cell death.
Gene Fusions in Medical Contexts
Gene fusions play an important role as drivers in various diseases, particularly cancers. The BCR-ABL1 fusion gene is a defining feature of chronic myeloid leukemia and some acute lymphoblastic leukemias, where its presence drives uncontrolled white blood cell growth. Another example is the EML4-ALK fusion, found in a subset of non-small cell lung cancers, which leads to continuous activation of a growth-promoting pathway.
Identifying specific gene fusions is becoming increasingly important in clinical diagnostics. Their presence can help classify a disease more precisely, providing insights beyond traditional pathological classifications. Gene fusions can also serve as prognostic markers, offering predictions about how a disease might progress or how a patient might respond to certain treatments. This genetic information helps guide personalized medicine approaches.
Detecting and Treating Gene Fusions
Detecting gene fusions involves specialized genetic testing methods that analyze a patient’s DNA or RNA. Techniques like fluorescence in situ hybridization (FISH) can visualize chromosomal rearrangements directly, while polymerase chain reaction (PCR) can amplify specific fusion transcripts if their sequences are known. Next-generation sequencing (NGS) is a more comprehensive approach, allowing for the simultaneous detection of many known and novel gene fusions across the genome.
The knowledge of specific gene fusions has significantly advanced the development of targeted therapies. These therapies are designed to specifically inhibit the activity of the abnormal fusion protein, rather than broadly affecting all cells. For example, drugs like imatinib specifically target the BCR-ABL1 fusion protein, blocking its uncontrolled activity in leukemia cells. This precision medicine approach leads to more effective treatments with fewer side effects compared to traditional chemotherapy.