A CALR mutation is a genetic alteration in the CALR gene, short for calreticulin. The CALR gene provides instructions for the calreticulin protein, which helps proteins fold correctly within the endoplasmic reticulum. This genetic change is acquired after birth, not inherited.
What Are CALR Mutations?
The CALR gene’s normal function extends beyond protein folding to include calcium regulation within cells, which impacts cell growth, division, and movement. A mutation in this gene involves the addition or removal of small amounts of genetic material, typically in a region called exon 9. This alteration leads to the production of an abnormal calreticulin protein with a different sequence of amino acids at one end.
These specific genetic changes are associated with a group of blood disorders known as myeloproliferative neoplasms (MPNs), characterized by the bone marrow overproducing blood cells. CALR mutations are the second most common genetic abnormality found in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), two types of MPNs. They are present in approximately 20-25% of adults with ET and 25-30% of adults with PMF. The significance of this mutation in these conditions lies in its ability to activate signaling pathways that drive the uncontrolled production of blood cells.
How CALR Mutations Affect Life Expectancy
The presence of a CALR mutation influences the prognosis and life expectancy for individuals with myeloproliferative neoplasms, particularly ET and PMF. Patients with CALR-mutated ET and PMF have distinct clinical characteristics and outcomes compared to those with other common mutations, such as JAK2 or MPL mutations. For instance, CALR-mutated ET patients tend to be younger, have lower white blood cell counts, and often present with higher platelet counts at diagnosis.
Also, CALR-mutated ET patients show a lower risk of thrombosis (blood clot formation) compared to those with the JAK2 mutation. While data for PMF are less clear, some studies suggest a decreased risk for thrombosis in CALR-mutated PMF as well. Overall survival is increased for CALR-mutated patients compared to those with the JAK2 V617F mutation.
The risk of disease progression, such as transformation from ET to myelofibrosis, can also be influenced by the CALR mutation type and its variant allele frequency (VAF). A high CALR VAF, particularly ≥60%, is associated with a shorter myelofibrosis-free survival, especially with type 1 CALR mutations. This suggests that the burden of mutated alleles can contribute to disease progression. Patients with CALR type 2 mutations, a 5-bp insertion, have a more favorable prognosis compared to those with type 1 mutations, a 52-bp deletion.
Detecting and Managing CALR-Associated Conditions
Detecting CALR mutations involves molecular genetic testing, performed on blood or bone marrow samples. This testing helps diagnose and classify myeloproliferative neoplasms. Accurate diagnosis is important for guiding patient management, as the presence of a CALR mutation can influence treatment decisions and prognosis.
Management strategies for MPNs associated with CALR mutations aim to control symptoms, prevent complications, and influence the disease course. These approaches are individualized, considering the specific MPN subtype, the patient’s symptoms, and their risk stratification. General strategies may include reducing excessive blood cell counts, managing symptoms like fatigue or splenomegaly, and preventing thrombotic events. Emerging therapies specifically targeting mutant CALR are also under investigation, aiming to selectively inhibit cancer-causing cells while preserving healthy ones.