BCR-ABL1 refers to a gene sequence found in an abnormal chromosome 22 of some people with certain forms of leukemia. Unlike most cancers, the cause of chronic myelogenous leukemia (CML) and some other leukemias can be traced to a single, specific genetic abnormality in one chromosome. The presence of the gene sequence known as BCR-ABL1 confirms the diagnosis of CML and a form of acute lymphoblastic lymphoma (ALL), specifically a type of B-lymphoblastic leukemia/lymphoma. In very rare cases, the abnormal chromosome is linked to cases of acute myeloid leukemia and T-lymphoblastic leukemia/lymphoma.
Humans have 23 pairs of chromosomes containing inherited genetic information. Those genes contain the blueprints, in the form of DNA, for producing the proteins that our bodies rely on to function properly. While some genetic abnormalities are inherited, they can also come from changes that occur to genes or chromosomes after a person is born. This can happen through exposure to various environmental factors (e.g., radiation, certain chemicals) but more often for unknown reasons.
The BCR-ABL1 gene sequence is one such acquired change that is formed when pieces of chromosome 9 and chromosome 22 break off and switch places. When this occurs, the ABL1 region in chromosome 9 fuses with the BCR gene region in chromosome 22. This type of change is called a reciprocal translocation and is often abbreviated as t(9;22). The resulting chromosome 22 that has the BCR-ABL1 gene sequence is known as the Philadelphia (Ph) chromosome because that is where it was first discovered.
The resulting Philadelphia chromosome contains an abnormal BCR-ABL1 fusion gene that encodes an abnormal protein that is responsible for the development of CML and a type of ALL. At diagnosis, 90-95% of cases of CML show a characteristic t(9;22) BCR-ABL1 reciprocal chromosomal translocation. About 30% of adults with B-ALL have the translocation, while it is only present in about 2 to 4% of cases in children.
The protein coded for by the abnormal BCR-ABL1 fusion gene is a type of enzyme called a tyrosine kinase. That enzyme is responsible for the uncontrolled growth of leukemic cells. When large numbers of abnormal leukemic cells start to crowd out the normal blood cell precursors in the bone marrow, signs and symptoms of leukemia start to emerge. Treatment of these leukemias typically involves a tyrosine kinase inhibitor (TKI).
Testing for BCR-ABL1 detects the Philadelphia chromosome and BCR-ABL1 fusion gene or its transcripts, which are the RNA copies made by the cell from the abnormal stretches of DNA. The presence of the BCR-ABL1 abnormality confirms the clinical diagnosis of CML, a type of ALL, and rarely acute myeloid leukemia (AML).
There are several different types of BCR-ABL1 tests available, including:
- Cytogenetics (chromosome analysis or karyotyping)
This test looks at chromosomes under a microscope to detect structural and/or numerical abnormalities. For example, the Philadelphia chromosome is a small abnormal version of chromosome 22 resulting from the exchange or translocation of material between chromosome 9 and chromosome 22. Cells in a sample of blood or bone marrow are grown in the laboratory and then examined to determine if the Philadelphia chromosome is present. Other chromosomal abnormalities can also be detected.
- Fluorescence in situ hybridization (FISH)
This test method uses fluorescent dye-labeled probes to "light up" the BCR-ABL1 gene sequence when it is present. Test results for FISH are often available more quickly than for conventional chromosome analysis.
- Genetic molecular testing (qualitative or quantitative)
Polymerase chain reaction (PCR)-based qualitative and quantitative tests detect and measure the BCR-ABL1 RNA transcripts in leukemia cells taken from blood or bone marrow samples. This test can detect very small amounts of BCR-ABL, even when the Philadelphia chromosome isn’t seen in bone marrow cells by less sensitive but important techniques like chromosome analysis or FISH.
- Secondary mutations within BCR-ABL1 are known to cause resistance to therapy. These can be detected by DNA sequencing methods.
How is the test used?
BCR-ABL1 testing is used to:
- Help diagnose some forms of leukemia, i.e., chronic myelogenous leukemia (CML) or a type of acute lymphoblastic leukemia (ALL) and, rarely, acute myeloid leukemia (AML) in which the BCR-ABL1 gene sequence is present (BCR-ABL1-positive).
- Monitor treatment
- Monitor for recurrence
- Detect resistance to therapy
BCR-ABL1 testing is ordered to detect the Philadelphia (Ph) chromosome and BCR-ABL1 gene sequence. Several types of tests may be ordered to detect BCR-ABL1. These include chromosome analysis, BCR-ABL1 molecular genetic test, and/or fluorescence in situ hybridization (FISH). These help establish the initial diagnosis of CML or Ph-positive ALL. The quantitative test is also used to monitor how well someone responds to therapy.
Tests for BCR-ABL1 are often performed along with other tests if a health practitioner suspects that someone has leukemia and is trying to diagnose or rule out CML and Ph-positive ALL.
The BCR-ABL1 can produce proteins of differing sizes and weights, depending on where the break in chromosome 22 occurred. In CML, the breakpoint in BCR is almost always in the major breakpoint cluster region (M-BCR), leading to the production of BCR-ABL1 protein of a larger size (the protein is called p210). Breaks in the minor breakpoint cluster region (m-BCR) leads to a shorter fusion protein (called p190), which is most frequently associated with Ph chromosome-positive ALL.
The quantitative BCR-ABL1 molecular test measures either of the breakpoints in the fusion gene. It is used to establish a baseline value and then to monitor the person's response to treatment and, if the person achieves remission, to monitor for recurrence. If treatment resistance or disease recurrence occurs, the BCR-ABL1 kinase domain mutation analysis should be performed to guide further treatment.
When is it ordered?
BCR-ABL1 testing is ordered when a health practitioner suspects that a person has CML or Philadelphia chromosome (Ph)-positive ALL. Initial testing may be indicated when a person has nonspecific signs or symptoms such as:
- Weight loss
- Joint or bone pain
- Enlarged spleen
- Night sweats
- As follow-up to abnormal findings on a complete blood count (CBC)
Early in the disease, a person may have few or no symptoms. As time passes and normal blood cells are crowded out of the bone marrow and the number of abnormal leukemic cells increases, a person may experience anemia, prolonged bleeding, and recurrent infections.
Once CML or Ph chromosome-positive ALL has been diagnosed, BCR-ABL1 quantitative genetic testing is ordered periodically (typically every 3 months) to monitor the response to treatment and monitor for recurrence.
When a person is not responding and treatment resistance is suspected or disease recurrence occurs after remission, BCR-ABL1 kinase domain mutation analysis may be performed.
What does the test result mean?
An interpretation of test results is typically done by a healthcare practitioner with specialized training and provided with the report.
If a person has abnormal white blood cells in the bone marrow and has the Philadelphia (Ph) chromosome and BCR-ABL1 gene sequence, then the individual is diagnosed with CML or Ph-positive ALL.
Of those who have CML, 90-95% have the Ph chromosome if tested by cytogenetics and 100% have the BCR-ABL1 gene sequence by FISH and/or qualitative BCR-ABL1 molecular testing. About 30% of adults with B-ALL and 2-4% of children with B-ALL are positive for the Ph chromosome and/or the BCR-ABL1 gene sequence.
A small percentage of people with CML will have the BCR-ABL1 gene sequence but not the Ph chromosome. These cases either have variant translocations that involve a third or even a fourth chromosome in addition to 9 and 22 or have a hidden translocation involving 9 and 22 that can not be identified by routine chromosomal analysis. Since the treatment for BCR-ABL1-related leukemias specifically targets the tyrosine kinase protein produced, these people can still be monitored with quantitative BCR-ABL1 molecular testing.
Very rarely, neither the Ph chromosome nor the BCR-ABL1 mutation can be found in people who seem to have CML. These people are considered to not truly have CML and might have unknown mutations causing the disease.
In general, if the amount of BCR-ABL1 in the blood or bone marrow decreases over time, then the person is responding to treatment. If the quantity of BCR-ABL1 drops below the test's detection level and the person's blood cell counts are normal, then the person is considered to be in remission.
Treatment response is frequently dramatic and long-lasting with imatinib, the first-generation tyrosine kinase inhibitor, but 30 to 40% of patients will need further treatment at some point. For many people, this is caused by the acquisition of point mutations in the tyrosine kinase domain of the BCR-ABL1 fusion gene. This leaves the protein insensitive to imatinib's inhibitory effects.
If the BCR-ABL1 level rises, then it indicates disease progression or recurrence and it may also indicate that the person has become resistant to imatinib. Additional genetic testing is often performed to detect the development of BCR-ABL1 kinase domain mutations associated with imatinib resistance.
If an individual's leukemia is resistant to imatinib, a second generation tyrosine kinase inhibitor may be given. Those tyrosine kinase inhibitors, developed after imatinib, are also given in case the side effects from imatinib are too severe or in case of a rare BCR-ABL mutation. They include ponatib, bosutinib, nilotinib, and dasatinib.
If a person with ALL is not positive for the Ph chromosome and the BCR-ABL1 gene sequence, then that person will not be given a tyrosine kinase inhibitor drug and BCR-ABL1 molecular testing cannot be used to monitor the person.
Is there anything else I should know?
- Chronic phase—most people with CML are diagnosed in the chronic phase, which usually has an insidious onset, meaning that leukemia symptoms may be absent or subtle. Patients have less than 10% immature blood cells (blasts) in blood or bone marrow samples.The chronic phase may last for a month to several years. This is the phase when there are few or no symptoms and also the time period when treatment is most successful.
- Accelerated phase—changes include but are not limited to increasing white blood cell (WBC) counts despite or unresponsive to therapy and additional changes to cells like an increase in blasts in blood and/or bone marrow (10-19% blasts), or additional chromosome abnormalities beyond the Philadelphia chromosome
- Blast phase—when blasts are 20% or more of the cells in the blood or bone marrow or when there is blast proliferation outside the bone marrow
Both blood and bone marrow are often evaluated as part of the initial diagnosis, but the majority of follow-up monitoring is performed on blood samples.
There is significant test variability among laboratories using different test platforms. Therefore, for a given patient, the quantitative BCR-ABL1 molecular testing should be performed by the same laboratory or referred to a laboratory that follows universal reporting criteria. Rising and falling levels of BCR-ABL1 are usually more important than a single test result.
Why would a chromosome analysis be done more than once?
Your health care provider may order chromosome analysis periodically to determine if you have developed any additional chromosome abnormalities. Additional changes are often seen with disease progression and acceleration.
If I have the Philadelphia chromosome and BCR-ABL1 gene, should my close family members be tested?
Should everyone with leukemia be tested?
Testing is only indicated when your health practitioner suspects that you have chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), or another rare form of leukemia, or wants to rule them out. The majority of people with leukemia will not have the Philadelphia chromosome and BCR-ABL1 fusion gene.
How long will it take for my results?
That depends of the specific test performed and the laboratory performing the test. BCR-ABL1 testing requires specialized equipment and expertise and your sample may be sent to a specialized hospital laboratory or a reference laboratory. It may take one to several days for your results to be available.
What is the difference between chronic myelogenous leukemia and chronic myeloid leukemia?