When you have abnormal results on a complete blood count (CBC) and your healthcare practitioner suspects that you may have a bone marrow disorder, especially essential thrombocythemia (ET) or primary myelofibrosis (PMF)
The calreticulin gene, called CALR for short, is responsible for making a protein called calreticulin. The exact function of calreticulin protein remains largely unknown, but it is likely involved in ensuring the correct folding of new proteins, maintaining correct calcium levels in cells, and a number of other cell functions. Mutations of the CALR gene are associated with bone marrow neoplasms that cause the production of too many blood cells. These blood disorders are collectively known as myeloproliferative neoplasms (MPNs). The CALR mutation test looks for abnormalities in the CALR gene to help diagnose and classify MPNs.
The MPNs most commonly associated with CALR mutations are:
- Essential thrombocythemia (ET)—there are too many platelet-producing cells (megakaryocytes) in the bone marrow
- Primary myelofibrosis (PMF), also known as chronic idiopathic myelofibrosis or agnogenic myeloid metaplasia—there are too many platelet-producing cells and cells that produce scar tissue in the bone marrow
CALR mutations are the second most common genetic abnormality (after JAK2 mutations) associated with essential thrombocythemia or primary myelofibrosis. They are present in about 20-25% of adults with ET and 25-30% of adults with PMF. Although rare and not well understood in children, 50% of pediatric PMF patients had CALR mutations.
The CALR mutation is acquired after birth as opposed to inherited. It is caused by the addition or removal of small amounts of genetic material to a region of the gene called exon 9. This leads to an abnormal calreticulin protein. It is not yet understood how the mutant protein leads to signs and symptoms of MPN. While more than 50 types of CALR mutation have been found, only the two most common variants associated with MPNs are included in conventional PCR testing. Next generation sequencing (NGS)-based analysis should detect all mutation variants but is not widely available.
In addition to helping diagnose MPNs, CALR mutation testing can provide information about a person's prognosis. Studies have shown that compared to individuals with the JAK2 mutation, those with the CALR mutation had a milder disease course, fewer signs and symptoms of blood clotting (thrombotic episodes), and better survival.
How is it used?
The CALR mutation test is used to help diagnose and classify bone marrow disorders that lead to the production of too many blood cells. These disorders are known as myeloproliferative neoplasms (MPNs).
CALR mutations are the second most common genetic abnormality associated with two types of MPNs: essential thrombocythemia (ET) and primary myelofibrosis (PMF).
Testing for genetic abnormalities associated with MPNs is generally done as follow-up if someone has a significantly increased hemoglobin, hematocrit, red blood cell and/or platelet count, or blood smear findings suggesting myelofibrosis, along with clinical signs and symptoms suggesting an MPN.
When is it ordered?
The CALR mutation test may be ordered, along with other tests, when a healthcare practitioner suspects that a person has a myeloproliferative neoplasm (MPN) such as essential thrombocythemia (ET) or primary myelofibrosis (PMF). It is typically tested after someone suspected of having an MPN has tested negative for a mutation of the BCR-ABL1 and JAK2 genes.
Sometimes people with MPNs may have no symptoms or a few, relatively mild ones that may be present for years before being recognized as an MPN, often during a routine physical. However, a healthcare practitioner may suspect an MPN and order testing when a person has abnormal results on a complete blood count (CBC) in combination with several signs and symptoms, such as:
- Enlarged spleen (splenomegaly) or liver (hepatomegaly), abdominal pain
- Excessive clotting (e.g., a blood clot in a vein or artery)
- Easy bruising or bleeding
- Headache, dizziness, vision problems
- Signs and symptoms related to anemia, such as fatigue and weakness
What does the test result mean?
A positive CALR mutation test means that the person likely has a myeloproliferative neoplasm (MPN), specifically essential thrombocythemia (ET) or primary myelofibrosis (PMF).
Other testing, such as a bone marrow biopsy, may need to be performed to determine which MPN the person has and to evaluate its severity.
About 20-25% of adults with essential thrombocythemia and 25-30% of adults with primary myelofibrosis have a CALR mutation. The mutation is also rarely found in people with chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML).
In 2016, the World Health Organization (WHO) revised its diagnostic criteria for MPNs. The presence of the CALR exon 9 mutation is one of three major criteria listed for diagnosis of ET and PMF.
Carrying a mutated CALR gene can have implications for an individual's MPN prognosis and disease progress. Studies have found that people with CALR mutations have better overall survival than those with JAK2 or myeloproliferative leukemia (MPL) mutations. People with CALR mutations also have a lower risk of harmful blood clots (thrombosis) than those with JAK2-positive ET.
A negative result typically means that the CALR mutation being tested for was not detected. It is possible to have a negative result and still carry an uncommon CALR mutation that the test cannot detect. It is also possible, though unlikely, that the test failed to detect a CALR exon 9 mutation. Note that next generation sequencing (NGS)-based analysis should detect all mutation variants in the CALR gene, but the test is not widely available.
A negative result does not rule out the possibility of having an MPN. Ten to 15 percent of essential thrombocythemia and primary myelofibrosis cases have no common genetic abnormality associated with them, i.e., negative for JAK2, CALR and MPL mutations (known as "triple-negative MPN").
Is there anything else I should know?
The discovery of genetic mutations underlying MPNs, beginning in 2005, represented a significant step forward in treating them. Drugs called targeted therapies designed to inhibit the abnormal proteins underlying the conditions show promise for being more effective than conventional MPN treatments. While targeted therapies have been developed to inhibit the JAK2 gene, CALR was discovered more recently and therapies to inhibit it are still being studied. Overall, developing targeted therapies to treat MPNs is a promising and active area of study.
Is the CALR mutation hereditary?
Can this test be done in my healthcare practitioner's office?
How long does it take for CALR mutation test results?
Are there other genetic mutations associated with MPNs?
Yes, JAK2 mutations are found in more than 95% of polycythemia vera (PV) cases. JAK2 mutations are also associated with 50-60% of cases of essential thrombocythemia (ET) and primary myelofibrosis (PMF). In addition, mutations in the myeloproliferative leukemia (MPL) gene are seen in a small percentage of adult ET and PMF patients, but not with PV. If someone carries the CALR mutation, that person will not carry JAK2 or MPL mutations, i.e., they are mutually exclusive. PV, ET and PMF are all rare in children and adolescents and although mutations might not be as common as in adults with these same diseases, not much is known. Genetic testing is also sometimes used to check for the presence or absence of a Philadelphia (Ph') chromosome or a BCR-ABL1 translocation in a person suspected of having chronic myeloid leukemia.