Calreticulin, or CALR, is a protein found within the body’s cells. It performs many important jobs, keeping cells healthy and functioning correctly. This protein is involved in fundamental processes that allow our cells to operate normally.
Primary Functions Within the Cell
Calreticulin primarily resides in the endoplasmic reticulum (ER), a complex network within cells responsible for making, folding, and sending out proteins. As an ER-resident protein, its main home is inside this cellular compartment.
Inside the ER, calreticulin acts as a molecular chaperone. Its job is to ensure that newly made proteins, especially glycoproteins, fold into their correct three-dimensional shapes. If a protein is misfolded, calreticulin helps prevent it from leaving the ER until it is properly formed, or it tags it for degradation.
Beyond protein folding, calreticulin is also involved in managing calcium levels within the ER. It binds to calcium ions, helping to store them within this cellular compartment. Proper calcium balance is important for many cellular processes, including muscle contraction, nerve communication, and various signaling pathways.
The Role of CALR Gene Mutations
A gene mutation is a change in the DNA instructions for making a protein. CALR gene mutations occur within exon 9, affecting the protein’s tail end. These changes are small deletions or insertions of genetic material.
These CALR gene mutations cause a “frameshift,” meaning the cell reads the DNA instructions incorrectly. This results in an altered calreticulin protein with a new tail segment that does not function as it should.
The altered calreticulin protein gains a new ability: it can bind to and constantly activate a receptor called MPL, found on the surface of blood-forming cells. This continuous activation sends incorrect signals, causing the bone marrow to produce too many blood cells.
Connection to Myeloproliferative Neoplasms
Myeloproliferative Neoplasms (MPNs) are a group of blood cancers originating in the bone marrow, where blood cells are made. In MPNs, the bone marrow produces an excessive number of one or more types of blood cells, such as platelets, red blood cells, or white blood cells.
CALR gene mutations are a cause of two specific MPNs: essential thrombocythemia (ET) and primary myelofibrosis (PMF). In ET, the bone marrow makes too many platelets. In PMF, there is an overgrowth of cells that produce scar tissue in the bone marrow.
CALR mutations are found in approximately 20-25% of adult patients with ET and 25-30% of adult patients with PMF. These mutations are “mutually exclusive” with other common genetic changes in MPNs, such as JAK2 or MPL mutations. This makes CALR a distinct diagnostic marker.
Clinical Testing and Prognosis
Doctors test for CALR mutations as part of the diagnostic process for suspected MPNs. Testing involves a blood draw, and DNA from blood cells is analyzed using genetic sequencing to look for alterations in the CALR gene. Detecting these mutations helps confirm an ET or PMF diagnosis.
A positive CALR mutation result provides important prognostic information. For individuals with ET and PMF, having a CALR mutation is associated with a more favorable prognosis compared to those with a JAK2 mutation. Patients with CALR mutations tend to have a lower risk of developing harmful blood clots.
Additionally, in patients with PMF, the presence of a CALR mutation is linked to better overall survival. This information helps doctors tailor management strategies and provides patients with a clearer understanding of their disease. Testing for CALR mutations has become a standard part of classifying these blood disorders.