The Philadelphia chromosome is a specific genetic abnormality found in the cells of individuals with certain types of leukemia. It involves a change in chromosome 22, where a piece of chromosome 9 has transferred to it. Discovered in Philadelphia in 1960, this genetic marker has advanced the understanding and treatment of associated cancers. Its presence indicates a genetic signature that drives uncontrolled cell growth in affected blood cells.
The Genetic Change
The Philadelphia chromosome arises from a precise genetic alteration: a reciprocal translocation between chromosome 9 and chromosome 22. A segment of the ABL1 gene from chromosome 9 breaks off and attaches to the BCR gene on chromosome 22. This exchange creates a shortened chromosome 22, the Philadelphia chromosome, and results in a new, abnormal fusion gene called BCR-ABL1.
The BCR-ABL1 fusion gene codes for an abnormal protein with enhanced tyrosine kinase activity. Tyrosine kinases are enzymes that act like “on” switches for many cellular processes, including cell growth and division. The BCR-ABL1 protein is constitutively active, meaning it is “always on.” This leads to uncontrolled cell proliferation and inhibits normal cell death. This continuous signaling drives the rapid and uncontrolled growth of immature white blood cells, which then accumulate in the blood and bone marrow.
Related Blood Cancers
The Philadelphia chromosome is most frequently associated with chronic myeloid leukemia (CML), present in the bone marrow cells of a large majority of CML patients. CML is a slow-developing cancer of the bone marrow where immature blood cells accumulate, crowding out healthy bone marrow cells. The BCR-ABL1 fusion gene drives CML.
This genetic abnormality is also observed in some cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Philadelphia chromosome-positive ALL, often referred to as Ph+ ALL, is a more aggressive form of acute leukemia, accounting for about 25% of adult ALL cases and 1-3% of childhood ALL cases. In these acute leukemias, the presence of the Philadelphia chromosome contributes to rapid disease progression and influences treatment approaches.
Identifying the Chromosome
Detecting the Philadelphia chromosome involves several diagnostic methods that analyze a patient’s blood or bone marrow cells.
Karyotyping
Karyotyping visualizes chromosomes under a microscope to identify structural abnormalities, such as the shortened chromosome 22 characteristic of the Philadelphia chromosome. This method allows for direct observation of the chromosomal translocation.
Fluorescence In Situ Hybridization (FISH)
FISH uses fluorescent probes that bind to specific DNA sequences on chromosomes. It detects the BCR-ABL1 fusion gene by showing the close proximity or fusion of the BCR and ABL1 gene signals. FISH can identify the fusion gene in both dividing and non-dividing cells, making it useful when traditional karyotyping is difficult due to a low number of dividing cells.
Polymerase Chain Reaction (PCR)
PCR, particularly reverse transcription-PCR (RT-PCR), is a molecular test used to detect the BCR-ABL1 fusion gene. This method amplifies specific RNA sequences, allowing for detection of the fusion transcript even at very low levels. PCR is highly sensitive and can quantify the amount of BCR-ABL1 genetic material, useful for diagnosis and monitoring treatment response.
Targeted Therapies and Management
Treatment for Philadelphia chromosome-positive diseases primarily uses targeted therapies, specifically tyrosine kinase inhibitors (TKIs). These medications, such as imatinib and dasatinib, work by blocking the activity of the abnormal BCR-ABL1 protein. By inhibiting the overactive tyrosine kinase, TKIs interfere with the uncontrolled growth signals that drive leukemia cells, improving patient outcomes.
TKIs are often the first-line treatment for chronic myeloid leukemia, transforming it into a manageable condition for many patients. For Philadelphia chromosome-positive acute lymphoblastic leukemia, TKIs are frequently combined with chemotherapy. Newer approaches also explore combinations with immunotherapy. These combinations aim to achieve deep molecular responses, where the BCR-ABL1 gene becomes undetectable.
While TKIs are effective, stem cell transplantation, also known as allogeneic hematopoietic stem cell transplantation (alloHSCT), remains an option for certain patients. This procedure involves replacing the patient’s diseased bone marrow with healthy stem cells from a donor. Transplantation may be considered for patients who do not respond well to TKI therapy, experience disease progression, or have high-risk features. Its role is continually being re-evaluated with the advent of more potent targeted therapies.