CALRmutant

CALRmutant refers to mutations in the CALR gene that drive certain myeloproliferative neoplasms (MPNs), most notably essential thrombocythemia and primary myelofibrosis. These mutations are typically somatic and occur in exon 9, producing a novel C-terminal region of calreticulin. Two common classes are type 1 (a 52-base-pair deletion) and type 2 (a 5-base-pair insertion), with numerous other, less frequent variants described.

CALR mutations are generally mutually exclusive with JAK2 and MPL mutations and are more often found in patients who are JAK2-negative. Detection relies on targeted DNA sequencing of CALR exon 9 and is used in parallel with testing for JAK2 V617F and MPL mutations as part of the diagnostic workup for MPNs.

Pathophysiologically, mutant CALR binds to the MPL thrombopoietin receptor and activates the JAK-STAT signaling pathway in a ligand-independent manner, promoting clonal proliferation of hematopoietic cells. This mechanistic link underpins the clinical phenotypes observed in CALR-mutant MPNs.

Clinically, CALR-mutant disease shows distinct features by diagnosis. In essential thrombocythemia, CALR-mutant patients tend to be younger and may have higher platelet counts, with a generally lower thrombotic risk compared with JAK2-mutant ET. In primary myelofibrosis, CALR mutations, particularly type 1-like mutations, are associated with a more favorable prognosis than JAK2-mutant PMF, though outcomes vary with mutation type and other prognostic factors.

Understanding CALRmutant status informs prognosis and risk stratification within MPNs and complements other molecular and clinical data used to guide management.