The most frequent genetic mutation in BCR-ABL1-negative myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), and primary myelofibrosis (PMF) is the JAK2V617F mutation, which is present in approximately 50% to 60% of patients. It serves as a confirmatory molecular marker of these diseases. Mutations in the MPL gene are found in an additional 5% to 10% of ET and PMF cases. It was recently discovered that somatic mutation (insertions and deletions) in exon 9 of the CALR gene is the second most frequent somatic mutation after JAK2 in ET and PMF patients, and it is mutually exclusive of JAK2 and MPL mutations.(1,2) It has a frequency of approximately 49% to 88% in JAK2 and MPL-wild type (WT) ET and PMF, and is not found in polycythemia vera (PV) patients.(1-4) Therefore, CALR mutation serves as an important diagnostic molecular marker in ET and PMF.
The CALR gene encodes for calreticulin, a multifunctional protein with a C-terminus rich in acidic amino acids and a KDEL ER-retention motif. All the pathologic CALR mutations reported to date are out-of-frame insertion and/or deletions (indel) in exon 9, generating a 1 base-pair (bp) frame shift and a mutant protein with a novel C-terminus rich in basic amino acids and loss of the KDEL ER-retention signal. The most common mutation types are 52-bp deletion (c.1092_1143del, L367fs*46) and 5-bp insertion (c.1154_1155insTTGCC, K385fs*47), and they comprise approximately 85% of CALR mutations in MPN.(1,2) CALR mutations have been found in hematopoietic stem and progenitor cells in MPN patients(2) and may activate the STAT5 signaling pathway.(1) They are associated with decreased risk of thrombosis in ET (1,3-5), and better survival in PMF compared to JAK2 mutations.(5)