Summary

• BCR-ABL1 is the name given to a genetic alteration that is linked to certain types of leukemia, a blood cancer.
• Unlike most cancers, the cause of these types of leukemia can be traced to a single, specific genetic abnormality known as the Philadelphia chromosome.
• It occurs when two genes BCR and ABL fuse together.
• A BCR-ABL1 test looks for the fused gene in a sample of blood or bone marrow.

What is BCR-ABL1?

The abnormal BCR-ABL1 gene is made when two separate genes, BCR and ABL, merge together and become one gene in a process called gene fusion. This altered gene is seen in people who have certain types of blood cancer:

• chronic myeloid leukaemia (CML)
• some cases of acute lymphoblastic leukaemia (ALL)
• acute myeloid leukaemia (rarely).

A quick look at genes and chromosomes

Genes give the instructions to make proteins that tell your body how to function. Genes are short sections of DNA. DNA is packaged into structures called chromosomes that can be found at the centre of your cells. Normally, each cell has the same set of 23 pairs of chromosomes – 46 chromosomes. One copy of each of the pair comes from your mother in the egg and the other copy comes from your father in the sperm. Everyone has 22 pairs of chromosomes which are the same in both males and females (these are called autosomes). In addition to these 22 pairs, everyone also have one pair of sex chromosomes - a pair of X chromosomes in females (XX) and one X and one Y in males (XY).

Although we can inherit some gene mutations, other types of mutations occur during the normal course of life. These are called acquired or somatic gene mutations.

Our cells have a lifespan – they get old and die off. Before they die, they make new copies of themselves, and this can lead to copying mistakes being made. Gene mutations can also occur because of environmental factors like smoking, ultraviolet radiation (sunlight) and certain chemicals. Normally, our immune system gets rid of these altered genes but as we age it gets less good at this.

How the BCR-ABL1 genetic change happens

Scientists have numbered chromosome pairs from 1 to 22, with the 23rd pair labelled as XX or XY.

The abnormal BCR-ABL1 gene is a fusion of the BCR and ABL genes, formed when pieces of chromosomes 9 and 22 break off and swap places. This mostly occurs during cell division – as the cell is replicating itself to make a new one.

The piece of chromosome 9 includes part of the ABL1 gene. It attaches to part of the BCR gene on chromosome 22. This makes the abnormal fusion gene, BCR-ABL1. This type of change is called a reciprocal translocation and is often abbreviated as t (9;22). 
This leaves a chromosome 22 that's shorter than normal. The changed chromosome 22 is known as Philadelphia (Ph) chromosome – named after the city where researchers first discovered it.

Because this is an acquired gene change you don't inherit it from your parents, and you cannot pass it on to your children.

The effects of the BCR-ABL1 fusion

Our genes control the way our body works by sending instructions to make proteins – the body’s building blocks. If a gene is altered, it can affect the structure, function and amount of the proteins being made.

Certain genes that promote cell growth and division are called oncogenes. Others that slow down cell division or trigger cells to die at the right time are called tumour suppressor genes. Cancers can be caused by changes in DNA that turn on oncogenes or turn off tumour suppressor genes.

The BCR-ABL1 fusion gene is an oncogene which sends instructions to make an abnormal signalling protein. This signalling protein is called tyrosine kinase, and it becomes abnormally and permanently switched on. This causes cells in the bone marrow to grow and divide out of control and leukaemia develops.

Blood cells are made in the bone marrow which is the spongy tissue in the middle of some of your bones, and normally they start out as stem cells and gradually mature into different types of blood cells. When they are affected by the BCR-ABL1 fusion gene and multiply in an uncontrolled way, they do not mature as they should. Because they have not matured properly, they cannot function normally.

As large numbers of abnormal leukaemic cells start to crowd out the normal blood cells in the bone marrow, signs and symptoms of leukaemia start to emerge.

Treatment of these leukaemias typically involves a tyrosine kinase inhibitor (TKI) such as Imatinib (Glivec®), given as daily oral tablets. This blocks the action of the abnormal signalling protein.

Why get tested?

BCR-ABL1 testing is requested if it is suspected that you may have CML or Philadelphia chromosome (Ph)-positive ALL. The Philadelphia chromosome is found in the bone marrow cells of almost all people with CML and some people with ALL. Rarely, it is seen with acute myeloid leukemia (AML). In a very small number of people, the leukemia cells have the BCR-ABL1 oncogene but not the Philadelphia chromosome.

BCR-ABL1 testing is used to:

• help diagnose CML, ALL or very rarely AML,
• monitor treatment to make sure it is working,
• check to make sure the leukaemia has not returned, and
• investigate treatment resistance.

Types of tests for BCR-ABL1 and the Philadelphia chromosome

Testing detects the Philadelphia chromosome, the BCR-ABL1 fusion gene, or BCR-ABL1 transcripts. These transcripts are RNA copies of the BCR-ABL1 made by the affected blood cell that act as a messenger carrying the gene's protein-making information.

There are several different types of tests:

Chromosome studies 
This test looks at chromosomes under a microscope to look for changes in the structure or number of chromosomes. Cells in a sample of blood or bone marrow are grown in the laboratory and then examined to see if the Philadelphia chromosome is there. Other chromosomal abnormalities can also be detected.

Fluorescence in situ hybridization (FISH)

This test uses two different coloured fluorescent dye-labelled probes to light up the BCR and the ABL1 genes. Cells are examined under a microscope to see where the different coloured probes are located. They should appear in separate locations but if there is a BCR-ABL1 translocation, the coloured dots will be fused together.

Molecular testing

PCR (polymerase chain reaction) molecular genetic testing is the most sensitive test for BCR-ABL1.

It detects and measures the number of copies of BCR-ABL1 sequence of the gene in your blood and/or bone marrow samples. This test is used to monitor your response to treatment with TKIs. It is also used to diagnose the small number of people who test negative for the Philadelphia chromosome.

ABL1 mutation testing.

Secondary mutations can arise within BCR-ABL1 in the kinase domain. This is part of the protein responsible for causing CML and some ALLs. These mutations can be detected by DNA sequencing methods. They may be responsible for treatment resistance to the TKIs. If your response to treatment is not as good as expected, testing for secondary mutations may tell your doctor which TKI treatment will be more effective.

Choice of tests

Chromosome studies, PCR and/or FISH testing are requested to help establish the initial diagnosis of CML and Ph-positive ALL.

Chromosomal studies and FISH can help to assess what percentage of your blood or bone marrow cells are affected.

PCR is a useful test to show where the breakpoint of the BCR-ABL1 fusion gene occurs in chromosome 22. This is important because it is different for CML and Ph-positive ALL. Each condition requires a different approach to treatment.

Having the test

Sample

Blood or a bone marrow sample collected using a bone marrow aspiration and/or biopsy procedure. Both blood and bone marrow are often evaluated as part of the initial diagnosis, but most follow-up monitoring is performed on blood samples.

Preparation

None

Your results

Diagnosis

If you have abnormal white blood cells in the bone marrow and have the Ph chromosome and BCR-ABL1 fusion gene, you will be diagnosed with CML or Ph-positive ALL.

• CML: All people with CML have the BCR-ABL1 fusion gene and about 90 - 95 per cent have the Ph chromosome.
• ALL: About 25 percent of adults with ALL and a small percentage of children with ALL have the BCR-ABL1 fusion gene and/or the Ph chromosome.

Prognosis (likely progression)

• CML: The prognosis for CML depends on the response to treatment. If, with treatment, you have a rapid reduction in BCR-ABL1 levels, you can achieve a good outcome, but if the BCR-ABL1 level is greater than 10 per cent at three months of treatment the prognosis is poorer.
• ALL: The prognosis for Ph-positive ALL is more complicated and can be influenced by the response to treatment, the amount of residual disease after treatment, and the presence of additional genetic mutations.

Very rarely some people thought to have CML do not have either the Ph chromosome or a BCR-ABL1 mutation. This means that other gene mutations may be causing the symptoms so a classification of true CML may not be made.

Treatment monitoring

PCR testing is used for the initial diagnosis to establish a baseline measurement and then it can be repeated periodically to monitor your response to treatment and monitor for recurrence.

• If the amount of BCR-ABL1 in the blood or bone marrow decreases over time, you are responding to treatment.
• If the amount of BCR-ABL1 drops below the test's detection limit and your blood cell counts are normal, you are considered to be in remission.
• If the BCR-ABL1 level rises, the leukaemia may be getting worse or returning. Another explanation is that you have become resistant to the type of TKI being used in treatment. Additional genetic testing is often performed to detect the development of BCR-ABL1 kinase domain mutations associated with resistance to different types of TKIs. Depending on the mutation identified, a different TKI may be used.

If you have been diagnosed with ALL but you do not have the Ph chromosome or the BCR-ABL1 fusion gene, you will not be given a TKI drug and BCR-ABL1 molecular testing cannot be used to monitor your condition. Other drugs will be used for treatment and the disease monitored by different tests such as flow cytometry, chromosome testing and genetic testing.

Your medical team may request chromosome studies periodically to check if you have developed any additional chromosome abnormalities. Additional changes are often seen with disease progression and acceleration

More to know?

Laboratories use different testing platforms. Therefore, the measurement of the amount of BCR-ABL1 in your blood 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.

BCR-ABL1 testing attracts a Medicare rebate when used in the diagnosis and monitoring of patients with laboratory evidence of certain types of leukaemia.

Questions to ask your doctor

The choice of tests your doctor makes will be based on your medical history and symptoms. It is important that you tell them everything you think might help.

You play a central role in making sure your test results are accurate. Do everything you can to make sure the information you provide is correct and follow instructions closely.

Talk to your doctor about any medications you are taking. Find out if you need to fast or stop any particular foods, medications or supplements. These may affect your results. Ask:

• Why does this test need to be done?
• Do I need to prepare (such as fast or avoid medications) for the sample collection?
• Will an abnormal result mean I need further tests?
• How could it change the course of my care?
• What will happen next, after the test?

More information

Pathology and diagnostic imaging reports can be added to your My Health Record. You and your healthcare provider can now access your results whenever and wherever needed.

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