CALR

CALR refers to calreticulin, a gene that encodes a multifunctional protein of the endoplasmic reticulum. Calreticulin is a calcium-binding molecular chaperone that assists in protein folding and quality control for glycoproteins and helps regulate intracellular calcium homeostasis. It has distinct structural regions—the N-terminal domain, a proline-rich P-domain, and a C-terminal acidic region—and it contains an endoplasmic reticulum retention signal at the C-terminus (KDEL in humans), which keeps the protein within the ER.

Mutations in CALR are most notable in myeloproliferative neoplasms (MPNs), particularly essential thrombocythemia and primary myelofibrosis, and are most often found in patients who lack JAK2 or MPL mutations. The pathogenic CALR mutations occur largely in exon 9 and are mainly frameshift mutations. The two common classes are type 1, a 52-base-pair deletion, and type 2, a 5-base-pair insertion. These mutations generate a novel C-terminus and alter the protein's function, promoting constitutive signaling through the MPL receptor and the downstream JAK-STAT pathway, which drives megakaryocyte proliferation and associated disease features.

Clinically, CALR-mutant ET and MF show distinct phenotypes and prognostic implications compared with JAK2- or MPL-mutant disease. CALR mutations are associated with differences in thrombotic risk and overall survival in some cohorts, and type 1- and type 2-like CALR mutations can correlate with different clinical outcomes. CALR mutations are typically detected through sequencing-based testing and have become an important biomarker in MPN diagnosis and prognosis.

Discovery of CALR mutations in MPNs occurred independently in 2013 in patients lacking JAK2 mutations, marking a significant advancement in the genetic understanding of these diseases.