The BCR-ABL1 gene is an abnormal genetic alteration arising from a specific change in the chromosomes within a cell. This genetic modification results in the creation of a fusion gene, which is a combination of two distinct genes.
Origin and Role of BCR-ABL1
The BCR-ABL1 fusion gene emerges from a chromosomal rearrangement known as the Philadelphia chromosome (Ph chromosome). This abnormality involves a balanced reciprocal translocation, where segments of chromosome 9 and chromosome 22 break off and swap places. The ABL1 gene from chromosome 9 moves to chromosome 22, joining with the BCR gene, forming the derivative Philadelphia chromosome.
The normal ABL1 gene on chromosome 9 provides instructions for a protein that acts as a tyrosine kinase. This enzyme regulates various cellular processes, including cell growth, division, differentiation, and controlled cell death, by adding phosphate groups to other proteins. The normal BCR gene on chromosome 22 also plays a role in cellular functions.
When the BCR and ABL1 genes fuse, they create the BCR-ABL1 fusion gene, which produces an abnormal, overactive tyrosine kinase protein. This chimeric protein is “always on” and does not require external signals to activate it, unlike the normal ABL1 kinase. This persistent activity leads to uncontrolled cell division, inhibits normal cell differentiation, and prevents programmed cell death.
Connection to Chronic Myeloid Leukemia
The BCR-ABL1 fusion gene is directly linked to Chronic Myeloid Leukemia (CML), serving as the defining genetic abnormality and primary driver of the disease. CML is a type of cancer that originates in the blood-forming cells of the bone marrow and results in the overproduction of abnormal white blood cells.
The constant activity of the BCR-ABL1 tyrosine kinase leads to continuously activated signaling pathways within the cells. These pathways, such as RAS/MAPK, PI3K/AKT, and JAK/STAT, promote uncontrolled cell proliferation and survival, while inhibiting apoptosis, the natural process of cell death. This disruption allows immature white blood cells to accumulate in the blood and bone marrow.
The BCR-ABL1 oncogene transforms pluripotent hematopoietic stem cells, precursors to all blood cells, into leukemic cells. This leads to their accumulation in the bone marrow and peripheral blood. The kinase also induces genomic instability, contributing to additional genetic changes that advance the disease.
Diagnosis and Monitoring
Detecting the BCR-ABL1 gene is fundamental for diagnosing CML and for tracking how well treatment is working. Two primary methods used for this are Polymerase Chain Reaction (PCR) and Fluorescence In Situ Hybridization (FISH) tests.
Quantitative PCR (qPCR) tests are highly sensitive and can measure the level of BCR-ABL1 gene transcripts in a patient’s blood or bone marrow. This allows for a baseline measurement at diagnosis and subsequent monitoring of treatment response, often every three months initially. A significant reduction in BCR-ABL1 levels indicates a good response to therapy.
FISH tests are employed to detect the Philadelphia chromosome and the BCR-ABL1 fusion gene. These tests identify the characteristic 9;22 translocation and are useful for confirming diagnosis and monitoring during treatment. While PCR offers greater sensitivity for quantifying residual disease, FISH confirms the abnormality’s presence.
Targeted Therapy
Targeted therapy, particularly with Tyrosine Kinase Inhibitors (TKIs), is the main treatment approach for CML patients with the BCR-ABL1 gene. TKIs are medications designed to specifically target and block the activity of the abnormal BCR-ABL1 protein. Unlike traditional chemotherapy, targeted therapies aim to attack cancer cells while minimizing damage to healthy cells.
The BCR-ABL1 protein functions as an overactive tyrosine kinase, constantly signaling cells to grow and divide. TKIs work by binding to the ATP-binding site of the BCR-ABL1 kinase, which prevents the enzyme from adding phosphate groups to its target proteins. This action “turns off” the continuous signaling, stopping the uncontrolled proliferation of leukemic cells and promoting their death.
The introduction of TKIs has significantly improved the outlook for CML patients. These medications have revolutionized CML treatment, leading to high rates of complete cytogenetic and molecular responses. This success highlights the effectiveness of therapies that specifically address the underlying genetic abnormality driving the disease.