The CALR exon 9 mutation refers to a specific genetic change within the CALR gene, which provides instructions for making the calreticulin protein. This mutation is not inherited but rather acquired during a person’s lifetime. It is recognized for its connection to certain blood disorders, particularly a group known as myeloproliferative neoplasms (MPNs). Understanding this genetic alteration helps in identifying and managing these conditions.
Understanding the CALR Exon 9 Mutation
The CALR gene is located on chromosome 19 and contains nine exons. It provides instructions for creating the calreticulin protein, found in various parts of the cell, including the endoplasmic reticulum (ER), cytoplasm, and cell surface. Within the ER, calreticulin plays a role in ensuring that newly formed proteins fold correctly and helps maintain appropriate calcium levels. The protein also influences gene activity, cell growth, and movement.
A gene is made up of segments, and exons are the coding portions that contain the instructions for building a protein. The CALR exon 9 mutation involves an insertion or deletion of genetic material within exon 9. This change leads to a “frameshift,” which alters the reading frame of the genetic code and results in the production of an abnormal calreticulin protein with a different end sequence.
These somatic mutations occur in early blood-forming cells. Over 50 types of CALR mutations have been identified, but the most common are a 52-base pair deletion (Type 1) and a 5-base pair insertion (Type 2), which collectively account for about 85% of cases.
Associated Blood Disorders
Myeloproliferative Neoplasms (MPNs) are bone marrow disorders characterized by the overproduction of one or more types of blood cells. CALR mutations are the second most common genetic abnormality, after JAK2 mutations, associated with these conditions.
The two main MPNs linked to the CALR exon 9 mutation are Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). Essential Thrombocythemia involves the bone marrow producing too many platelet-making cells (megakaryocytes), leading to an excess of platelets. Approximately 20-25% of adults with ET have a CALR mutation.
Primary Myelofibrosis (PMF) involves overproduction of platelet-making cells and scar tissue in the bone marrow. This scarring can disrupt normal blood cell production. CALR mutations are present in about 25-30% of adults with PMF. The abnormal calreticulin protein caused by the CALR mutation is thought to activate the JAK-STAT signaling pathway, which can lead to uncontrolled growth of blood-forming cells and an overproduction of platelets.
Symptoms for ET can include an increased risk of blood clots, while PMF may present with fatigue, an enlarged spleen, and anemia due to bone marrow scarring. Patients with CALR mutations often have a lower white blood cell count and better overall survival compared to those with JAK2 mutations. They also tend to have a lower risk of harmful blood clots than individuals with JAK2-positive ET, though there might be a higher bleeding risk.
Detecting the Mutation
Detecting the CALR exon 9 mutation requires genetic testing, typically on blood or bone marrow samples. Molecular diagnostic techniques pinpoint these genetic changes. The most common methods include PCR-based assays, which amplify specific DNA regions to detect insertions or deletions, and next-generation sequencing (NGS), which can identify a broader range of mutation variants.
Testing for the CALR mutation is an important part of the diagnostic process for suspected MPNs, especially when other common mutations, such as JAK2 or MPL, are not present. The presence of a CALR exon 9 mutation is one of the major criteria used for diagnosing ET and PMF. This testing aids in distinguishing MPNs from other conditions and helps guide the prognosis and clinical course for individuals.
A positive test result for the CALR mutation indicates the likelihood of an MPN, specifically ET or PMF. However, additional evaluations, such as a bone marrow biopsy, may be necessary to confirm the specific type of MPN and assess its severity. The testing helps provide a more complete picture of the genetic landscape of the disease.
Managing the Condition
Management of MPNs associated with the CALR exon 9 mutation is individualized, taking into account the specific MPN subtype, patient symptoms, risk factors, and the particular mutation present. Treatment strategies aim to control symptoms, reduce complications, and improve quality of life. Patients with CALR mutations have a more favorable prognosis compared to those with JAK2 mutations, often with a lower risk of blood clots but potentially a higher risk of bleeding.
For Essential Thrombocythemia, common approaches may involve low-dose aspirin to reduce the risk of blood clots, or cytoreductive therapies such as hydroxyurea or interferon to lower blood cell counts. These medications help manage the excessive production of platelets. Close monitoring of blood counts and symptoms is a regular part of care.
For Primary Myelofibrosis, management can include JAK inhibitors like ruxolitinib, which target the overactive signaling pathways contributing to the disease. In certain cases, particularly for younger patients or those with more advanced disease, a stem cell transplant may be considered as a potentially curative option. Regular medical care and ongoing collaboration with a hematologist are important for adjusting treatment as needed and managing any emerging symptoms.