CALR is a human gene that encodes the protein calreticulin, which helps fold proteins and manage calcium inside cells.
Mutations in the CALR gene are major drivers of blood cancers known as myeloproliferative neoplasms (MPNs), specifically essential thrombocythemia (ET) and primary myelofibrosis (PMF).
Calreticulin resides mainly in the endoplasmic reticulum (ER) to control protein quality, calcium storage, and cell signaling.
Mutation and Disease: Exon 9 mutations in CALR (such as Type 1 and Type 2 insertions/deletions) cause the mutant protein to travel to the cell surface, driving abnormal blood cell production.
CALR mutants find firmly to MPL and not to other cytokine receptors in the endoplastic reticulum.
Mutant CALR induces MPL dimerization and activation exclusively at the cell surface.
Much of mutant CALR protein is secreted and can stimulate the CALR muted clone in an autocrine or paracrine manner.
Mutant CALR can result in oncogenic activation of the MPL – JAK2 – STAT pathway and its downstream signaling.
CALR mutation can induce endoplasmic reticulum stress, disrupt endoplasmic reticulum, calcium homeostasis, and trigger a cellular response, the unfolded protein response.
Diagnostic Value: A CALR Mutation Test is used alongside JAK2 and MPL tests to diagnose and classify bone marrow disorders when patients have unexplained high platelet counts.