The BCR-ABL gene is an abnormal gene found in individuals with certain types of blood cancer. It is not an inherited gene but one that forms during a person’s life from a specific genetic error. This gene is a primary driver in most cases of chronic myeloid leukemia (CML) and some instances of acute lymphoblastic leukemia (ALL). The discovery of BCR-ABL provided a clear genetic target, which later allowed for the development of effective therapies that have transformed patient outcomes.
The Formation of a Fusion Gene
The BCR-ABL gene results from a structural error involving two chromosomes. The formation occurs through an event called a chromosomal translocation, where parts of two chromosomes swap places. Specifically, a section of chromosome 9 breaks off and trades places with a section of chromosome 22. This exchange is a reciprocal event, meaning both chromosomes are altered.
This specific translocation creates a visibly shortened chromosome 22, which was first identified by researchers in Philadelphia and is now known as the Philadelphia chromosome. The breakage on chromosome 9 happens within a gene called ABL1, while the break on chromosome 22 occurs in the BCR gene. When the broken piece of chromosome 9 attaches to chromosome 22, part of the ABL1 gene fuses directly to the BCR gene, creating the new hybrid BCR-ABL gene.
This fusion event is the direct cause of the subsequent problems. The new BCR-ABL gene combines the functional domains of two separate proteins into one. This resulting fusion protein has capabilities that neither of the original proteins normally possess. The presence of this Philadelphia chromosome is the defining characteristic of chronic myeloid leukemia.
How BCR-ABL Drives Cancer Growth
The protein created from the normal ABL1 gene is an enzyme called a tyrosine kinase. In a healthy cell, tyrosine kinases function as tightly regulated switches, sending signals that tell the cell when to grow, divide, and die. The ABL protein is activated only when specific signals are received, after which it is promptly switched off again.
The fusion of the BCR gene segment to the ABL1 gene fundamentally alters this regulation. The resulting BCR-ABL protein is a tyrosine kinase that is permanently stuck in the “on” position. It continuously sends powerful signals telling the cell to proliferate without stopping, leading to uncontrolled and rapid cell division.
This hyperactivity drives the development of leukemia. The bone marrow cells containing the BCR-ABL gene multiply excessively, crowding out healthy blood cells. These leukemic cells also have a survival advantage, as the BCR-ABL protein interferes with the natural process of programmed cell death, or apoptosis. This combination of rampant growth and refusal to die leads to the massive accumulation of abnormal white blood cells that characterizes CML.
Diagnostic and Detection Methods
Identifying the BCR-ABL gene is a central part of diagnosing specific leukemias. Doctors use several laboratory techniques to confirm its presence. The initial method, known as cytogenetics or karyotyping, involves creating a visual map of a patient’s chromosomes from a blood or bone marrow sample. This allows a technician to physically see the Philadelphia chromosome, the characteristically shortened chromosome 22.
A more targeted method is fluorescence in situ hybridization (FISH). This technique uses specially designed fluorescent probes that attach to the specific DNA sequences of the BCR and ABL genes. If the genes are in their normal positions, the fluorescent signals will appear separate. If the BCR-ABL fusion has occurred, the signals will appear together, providing clear visual proof of the translocation.
The most sensitive detection method is the polymerase chain reaction (PCR) test. This molecular test can find the specific genetic sequence of the BCR-ABL fusion gene itself, even if it is present in very small amounts. PCR works by amplifying, or making millions of copies of, the BCR-ABL genetic material from a patient’s sample. This amplification allows for the detection of the fusion gene at levels far too low to be seen with karyotyping or FISH.
Targeted Therapy and Patient Monitoring
The understanding of BCR-ABL as the driver of CML led to the development of drugs known as tyrosine kinase inhibitors (TKIs). This approach, called targeted therapy, involves using drugs designed specifically to interfere with the action of the BCR-ABL protein. TKIs are designed to block the hyperactive signaling of the cancer-causing protein, leaving most healthy cells unharmed.
The first such drug, imatinib, fits into a specific pocket on the BCR-ABL protein, effectively turning the stuck “on” switch to the “off” position. This action stops the protein from sending its growth signals, which in turn halts the uncontrolled proliferation of the leukemia cells. The success of imatinib in treating CML transformed the disease from a fatal diagnosis into a manageable chronic condition for most patients.
Since the introduction of imatinib, newer generations of TKIs have been developed. These second and third-generation drugs, such as dasatinib and nilotinib, are often more potent and can be effective in patients whose leukemia develops resistance. Resistance can occur when the BCR-ABL gene undergoes further mutations, changing the shape of the protein so that imatinib can no longer bind effectively.
Treatment with TKIs is closely linked with patient monitoring. Doctors use a quantitative version of the polymerase chain reaction test (qPCR) to measure the amount of the BCR-ABL gene transcript in a patient’s blood over time. The goal of treatment is to reduce the levels of BCR-ABL to undetectable or very low levels, a state known as a major molecular response. Regular qPCR monitoring allows doctors to track how well a therapy is working and make adjustments if needed.