Calreticulin is a protein found within cells that plays a role in various cellular processes. Genetic changes, known as mutations, in the gene responsible for calreticulin (CALR) can lead to health issues. These mutations can alter the protein’s normal functions, leading to abnormal cellular behavior.
Understanding Calreticulin’s Role
Calreticulin (CALR) is a multifunctional protein primarily located in the endoplasmic reticulum (ER), a network of membranes within eukaryotic cells. It acts as a calcium-binding chaperone, maintaining calcium balance within the cell, which influences cell signaling and proliferation. Calreticulin is also involved in the proper folding of newly synthesized glycoproteins, ensuring their correct structure. It contributes to cell adhesion and may also play a role in regulating gene expression within the nucleus.
How Calreticulin Mutations Arise
Calreticulin (CALR) mutations involve genetic changes, specifically insertions or deletions, within exon 9 of the CALR gene. The most common types are a 52-base pair deletion (Type 1) and a 5-base pair insertion (Type 2), accounting for over 80% of observed CALR mutations. These genetic alterations lead to a frameshift, altering the gene’s reading frame and producing an abnormal calreticulin protein.
This mutant protein often loses its KDEL motif, a signal that normally keeps it within the endoplasmic reticulum. Consequently, the altered calreticulin protein can be secreted from the ER and interact with signaling molecules on the cell surface. This abnormal interaction can activate signaling pathways, such as the JAK/STAT pathway, contributing to uncontrolled cell growth and proliferation. These CALR mutations are acquired after birth and are not inherited.
Connection to Blood Disorders
Calreticulin mutations are strongly associated with myeloproliferative neoplasms (MPNs), specifically essential thrombocythemia (ET) and primary myelofibrosis (PMF). These mutations are the second most common genetic changes found in ET and PMF, after JAK2 mutations. CALR mutations are present in approximately 20-25% of adults with ET and 25-30% of adults with PMF.
In essential thrombocythemia, the bone marrow produces too many platelets. This overproduction can lead to an increased risk of blood clots or, less commonly, bleeding problems. Patients with CALR-mutated ET generally have higher platelet counts but may experience a lower risk of thrombosis compared to those with JAK2 mutations.
Primary myelofibrosis is characterized by the gradual replacement of normal bone marrow tissue with scar-like material. This scarring impairs the bone marrow’s ability to produce sufficient healthy blood cells, leading to conditions like anemia and an enlarged spleen and liver. The altered calreticulin protein drives the overproduction of blood cells by activating the thrombopoietin receptor (MPL) and its downstream signaling, particularly the JAK-STAT pathway. This constitutive activation promotes the uncontrolled growth and survival of hematopoietic stem cells and progenitor cells, leading to the characteristic features of these MPNs. Type 1 CALR mutations are more frequently observed in PMF, while Type 2 mutations are predominantly associated with ET.
Detecting and Managing CALR-Mutated Conditions
Detecting CALR mutations is a standard part of diagnosing myeloproliferative neoplasms (MPNs). Genetic testing is performed on a blood sample or a bone marrow aspirate and biopsy. This testing involves molecular methods, such as PCR-based next-generation sequencing, which identify insertions or deletions in the CALR gene’s exon 9. These tests help differentiate MPNs from other conditions and guide treatment decisions.
Managing CALR-mutated MPNs involves controlling symptoms and preventing complications. For essential thrombocythemia, treatment often focuses on reducing platelet counts and lowering the risk of blood clots. For primary myelofibrosis, management may include therapies to address anemia, reduce spleen size, and alleviate other symptoms. Treatment plans are individualized based on a patient’s symptoms, risk factors, and the type of CALR mutation, as different mutation subtypes can influence clinical outcomes.