A gene can be thought of as a recipe for building a protein. When a spelling error, or mutation, occurs in that recipe, it can lead to a faulty protein linked to certain health conditions. The Calreticulin gene, or CALR, is one such recipe, and specific changes to its sequence are associated with a particular group of blood disorders.
The Role of the CALR Gene and Its Mutation
The CALR gene provides the instructions for making a protein called calreticulin. This protein has several jobs, primarily acting as a chaperone to ensure other newly formed proteins are folded into their correct three-dimensional shapes. It also helps manage calcium levels inside the endoplasmic reticulum, a structure involved in protein processing and transport.
A CALR mutation is not inherited but is acquired during a person’s lifetime, known as a somatic mutation. These mutations typically involve small insertions or deletions of genetic material in a part of the gene called exon 9. This change results in a frameshift, altering the genetic code and leading to an abnormal calreticulin protein. This altered protein is no longer retained in the endoplasmic reticulum as it should be.
The abnormal calreticulin protein interacts with and activates a receptor on the surface of blood stem cells called the thrombopoietin receptor (MPL). This constant activation turns on a signaling cascade inside the cell known as the JAK-STAT pathway. This pathway acts like an accelerator for cell production, and when it becomes stuck in the “on” position, it directs the bone marrow to produce an excessive number of blood cells.
Associated Myeloproliferative Neoplasms
The uncontrolled cell growth triggered by a CALR mutation leads to chronic blood cancers called myeloproliferative neoplasms (MPNs). These mutations are most frequently found in two specific types: Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). A CALR mutation is found in about 20-25% of adults with ET and 25-30% with PMF. These mutations are almost never seen in another MPN, polycythemia vera.
Essential thrombocythemia is a disorder defined by the overproduction of platelets, the blood cells responsible for clotting. While some individuals may have no symptoms, others can experience complications related to abnormal clotting, such as deep vein thrombosis or pulmonary embolism, or bleeding issues. Patients may also experience fatigue, headaches, or a burning sensation in the hands and feet.
Primary myelofibrosis is a more aggressive condition characterized by the buildup of scar tissue (fibrosis) in the bone marrow. This scarring disrupts the normal production of blood cells, leading to severe anemia, fatigue, and an enlarged spleen as it tries to take over blood cell production. Other common symptoms of PMF include fever, night sweats, bone pain, and weight loss.
The Diagnostic Process
The diagnostic process often begins when a routine complete blood count (CBC) reveals abnormalities. A physician might observe a persistently high platelet count, which would suggest a condition like essential thrombocythemia. It could also show various abnormalities in red and white blood cells that could point toward myelofibrosis.
To confirm an MPN and identify its genetic driver, molecular testing is performed on a sample of blood or bone marrow. Since mutations in the JAK2, CALR, and MPL genes are typically mutually exclusive, laboratories often test for them in a stepwise fashion. The presence of a CALR mutation is a diagnostic criterion for both ET and PMF according to the World Health Organization.
Techniques like polymerase chain reaction (PCR) are used to amplify the specific region of the CALR gene where mutations occur, allowing for precise detection. Identifying a CALR mutation helps diagnose the MPN and also distinguishes it from non-cancerous causes of high blood cell counts, which informs the prognosis and treatment plan.
Prognosis and Treatment Implications
A CALR mutation has significant implications for a patient’s long-term outlook. Within the spectrum of MPNs, having a CALR mutation is generally associated with a more favorable prognosis compared to the more common JAK2 mutation. Patients with CALR-mutated MPNs typically have a lower risk of thrombosis (dangerous blood clots), and the disease may also progress more slowly.
This improved prognosis influences the management strategy. For many patients with low-risk essential thrombocythemia, treatment may begin with a “watch and wait” approach combined with low-dose aspirin to reduce clotting risk. The goal of therapy is to manage symptoms and prevent major complications like stroke or heart attack, not to cure the disease.
In cases where blood cell counts are very high or symptoms are severe, cytoreductive therapy may be initiated. Medications such as hydroxyurea or interferon are used to lower the production of blood cells in the bone marrow. While these treatments can control cell counts and alleviate symptoms, they do not eliminate the mutated cells. The specific type of CALR mutation can also provide further prognostic detail, helping to refine risk assessment.