Also known as:Promyelocytic Leukemia/Retinoic Acid Receptor Alpha [PML-RARA t(15;17)(q22;q12)]
Formal name:[PML-RARA t(15;17)]
Related tests:Complete Blood Count; Bone Marrow Aspiration and Biopsy; Blood Smear; WBC Differential
Why Get Tested?
To help diagnose acute promyelocytic leukemia (APL), a type of acute myeloid leukemia (AML); to help guide and/or monitor treatment of APL or to monitor for recurrence
When to Get Tested?
When you have results of a CBC and/or signs and symptoms that suggest that you may have leukemia; periodically when you are being treated for APL and/or when you are in remission
A blood sample drawn from a vein in your arm or a bone marrow sample collected using a bone marrow aspiration and/or biopsy procedure
Test Preparation Needed?
How is it used?
This testing is used to detect the abnormal promyelocytic leukemia/retinoic acid receptor alpha or PML-RARA gene sequence. It is used to help diagnose acute promyelocytic leukemia (APL) in which the PML-RARA gene sequence is present, to guide treatment, to monitor response to treatment, and to monitor for disease recurrence.
A few different test methods are available to evaluate for PML-RARA, and they may be used for various purposes:
- Fluorescence in situ hybridization (FISH) may be used to help diagnose APL and/or help to determine the percentage of person's blood or bone marrow cells that are affected.
- A molecular test (polymerase chain reaction, PCR) may be ordered to help establish the initial diagnosis of APL. A PML-RARA PCR test is typically ordered at the time of the initial diagnosis to establish a baseline value and then periodically to monitor a person's response to treatment and, if the person achieves remission, to monitor for recurrence. PCR will only detect the PML-RARA fusion, not the more rare combination of RARA with another gene.
- A chromosome analysis may be used to help diagnose APL. This method can detect the more rare combination of RARA with a gene other than PML, so it may be used if one of the other test methods is negative but APL is still strongly suspected.
PML-RARA testing is often performed along with other blood and/or bone marrow tests if a doctor suspects that a person has leukemia and is trying to diagnose or rule out APL. Some of these other tests may include:
- Complete blood count (CBC)–evaluates the number of each type of blood cell
- Differential–identifies and counts different types of white blood cells
- Blood smear–blood cells are examined under a microscope
- Immunophenotyping–classifies cells according to the markers (antigens) on the surfaces of cells
When is it ordered?
Testing is ordered when a doctor suspects that a person has APL. Initial testing may be indicated when a person has abnormal findings on a CBC and/or blood smear such as an increased or decreased number of white blood cells, decreased platelets, decreased red blood cells, and abnormal, immature white blood cells called promyelocytes, and nonspecific symptoms that may be related to leukemia such as:
- Fatigue or weakness
- Pale skin (pallor)
- Unexplained weight loss
- Joint or bone pain and/or an enlarged spleen
- Excessive bleeding, bruising, or inappropriate blood clotting
Early in APL, 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. Those with APL may experience both bleeding and inappropriate clotting, with DIC (disseminated intravascular coagulation) as a potential life-threatening complication.
Once APL has been diagnosed, PML-RARA molecular testing is ordered periodically to monitor the response to treatment and monitor for recurrence.
A chromosome analysis may sometimes be ordered when a PML-RARA gene sequence is not detected and the doctor suspects another rearrangement involving the RARA gene may be present.
What does the test result mean?
If a person has abnormal promyelocytes in the blood and bone marrow and has the PML-RARA gene sequence, then the person is diagnosed as having APL.
The presence of PML-RARA means the individual will likely benefit from treatment with all-trans retinoic acid (ATRA). This is a drug that can help promyelocytic leukemia cells to continue maturing. ATRA is typically effective in those cases where the PML-RARA fusion gene is present. A small percentage of people with APL have a fusion between RARA and a different gene, and they may or may not benefit from ATRA therapy depending upon the gene involved.
When monitoring treatment, a decrease in the amount of PML-RARA in the blood or bone marrow over time means the person is responding to treatment. If the number of cells that have PML-RARA drops below the test's detection limit and the person's blood cell counts are normal, then the person is considered to be in remission. An increase in PML-RARA levels over time indicates disease progression or recurrence.
If a person with APL is not positive for the PML-RARA gene sequence, then that person may not be given ATRA therapy and PML-RARA molecular testing cannot be used to monitor the person.
Is there anything else I should know?
Both blood and bone marrow may be evaluated as part of the initial diagnosis, but follow-up monitoring is often performed on blood samples. There is significant test variability among laboratories using different test methods. Therefore, for a given person with APL, PML-RARA molecular testing should be done by the same laboratory. Rising and falling levels of PML-RARA are usually more important than a single test result.
What is being tested?
Promyelocytic leukemia/retinoic acid receptor alpha or PML-RARA refers to an abnormal gene sequence that is associated with a specific type of leukemia. This test detects and measures PML-RARA in the blood or bone marrow to determine if an individual has acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). PML-RARA represents the rearrangement of genetic material on two chromosomes.
Humans normally have 23 pairs of chromosomes, including 22 pairs of non-sex-determining chromosomes (also known as autosomes) and 1 pair of sex chromosomes (XX for females, XY for males). Chromosomes contain a person's inherited genetic information. The genes that reside there form the blueprints for the production of thousands of proteins. Sometimes changes can occur to a person's chromosomes and/or genes during their lifetime because of exposures to radiation, toxins, or for unknown reasons.
The PML-RARA gene sequence is one such acquired change (mutation) that is formed when pieces of chromosome 15 and chromosome 17 break off and switch places. The PML gene region in chromosome 15 then fuses with the RARA gene region in chromosome 17. This is referred to as reciprocal translocation, and this particular one is commonly expressed as t(15;17).
Normally, the PML gene codes for a protein that helps prevent uncontrolled cell growth and acts as a tumor suppressor. The RARA gene codes for a protein that is crucial for white blood cell (WBC) maturation, as these cells typically develop through several stages in the bone marrow before release into circulation. The mutated PML-RARA fusion gene codes for an abnormal fusion protein that does neither of these functions but instead leads to the uncontrolled production and accumulation of leukemic WBCs that do not mature or differentiate beyond the promyelocyte stage. As a large number of these abnormal cells start to crowd out the normal blood cell precursors in the bone marrow, signs and symptoms of leukemia start to emerge.
Up to 98% of cases of acute promyelocytic leukemia have a characteristic t(15;17) PML-RARA reciprocal chromosomal translocation. Occasionally, cases of APL have translocations involving the RARA gene and genes other than PML.
Testing detects the PML-RARA fusion gene or its transcripts, the RNA copies made by the cell from the abnormal gene sequence of DNA. The presence of the PML-RARA abnormality helps confirm the diagnosis of APL.
Testing can also help guide cancer therapy. Treatment of APL typically involves all-trans retinoic acid (ATRA), a drug that binds to retinoic acid receptors on cells. The drug can overcome the effect of the abnormal PML-RARA protein and allow the WBCs to continue maturing. This therapy works well in conjunction with chemotherapy but only in those cases where the PML-RARA fusion gene is present. The treatment results in remission in about 80-90% of these patients, according to the American Cancer Society. A small percentage of people with APL have a fusion between the RARA gene and a different gene, and they may or may not benefit from ATRA therapy dependending upon the specific gene involved.
There are several different types of PML-RARA tests available, including:
- Fluorescence in situ hybridization (FISH)
This test method uses fluorescent dye-labeled probes to "light up" the PML-RARA gene sequence when it is present. This method also determines the percentage of blood or bone marrow cells that contain the abnormal, fused PML-RARA gene. FISH can also be used to detect the variant translocations involving RARA and genes other than PML. This may help identify ATRA-resistant rearrangements.
- Genetic molecular testing
The polymerase chain reaction (PCR)-based tests detect and quantify PML-RARA gene transcripts, or gene product units, in a person's blood and/or bone marrow samples. The PML-RARA PCR test is quantitative, that is, it provides a general estimate of the number of PML-RARA gene sequences present.
- Chromosome analysis (cytogenetics or karyotyping)
This test method involves the evaluation of a person's chromosomes under a microscope to detect structural and/or numerical abnormalities. Cells in a sample of blood or bone marrow are examined to determine if the PML-RARA t(15;17) chromosome translocation is present. Other chromosomal abnormalities, such as translocations involving the RARA gene and genes other than PML can also be detected.
How is the sample collected for testing?
A blood sample is obtained by inserting a needle into a vein in the arm or a bone marrow sample is collected using a bone marrow aspiration and/or biopsy procedure.
NOTE: If undergoing medical tests makes you or someone you care for anxious, embarrassed, or even difficult to manage, you might consider reading one or more of the following articles: Coping with Test Pain, Discomfort, and Anxiety, Tips on Blood Testing, Tips to Help Children through Their Medical Tests, and Tips to Help the Elderly through Their Medical Tests.
Another article, Follow That Sample, provides a glimpse at the collection and processing of a blood sample and throat culture.
Is any test preparation needed to ensure the quality of the sample?
No test preparation is needed.
- Are there other genetic changes that my doctor may test for with leukemia?
Possibly. For example, the BCR-ABL fusion gene is a translocation genetic change that is associated with different chromosomes and different leukemias, namely chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL).
- If I have the PML-RARA gene, should my close family members be tested?
No. This genetic change is one that is acquired during a person's lifetime and is not inherited.
- Should everyone with leukemia be tested?
Testing is only indicated when your doctor suspects that you have APL or wants to rule it out. APL is a subtype of acute myeloid leukemia (AML). The majority of people with leukemia will not have the PML-RARA gene sequence.
- Can PML-RARA testing be done in my doctor's office?
PML-RARA testing requires specialized equipment and expertise. It must be performed by a specialized hospital laboratory or a reference laboratory.
© 2017 American Association for Clinical Chemistry, republished from Lab Tests Online.*
Descriptions of clinical laboratory tests were originally prepared for use on Lab Tests Online, an award-winning patient education website on clinical laboratory testing. Lab Tests Online is produced by the American Association for Clinical Chemistry (AACC), a global scientific and medical professional organization dedicated to clinical laboratory science and its application to healthcare. The Lab Tests Online website is developed in collaboration with other laboratory professional societies and is funded in part through corporate sponsorships.