Calreticulin (CALR) Mutation Analysis

The calreticulin (CALR) gene is somatically mutated in approximately 70% of patients with JAK2-negative essential thrombocythemia (ET) and 60% to 88% of patients with JAK2-negative primary myelofibrosis (PMF). Only a minority of patients (approximately 8%) with myelodysplasia have mutations in the CALR gene. CALR mutations are rarely detected in patients with de novo acute myeloid leukemia, chronic myelogenous leukemia, lymphoid leukemia or solid tumors. CALR mutations are not detected in polycythemia and generally appear to be mutually exclusive with JAK2 mutations and MPL mutations.

The majority of mutational changes involve a variety of insertion or deletion mutations in exon 9 of the calreticulin gene: Approximately 53% of all CALR mutations are a 52 bp deletion (type-1), while the second most prevalent mutation (approximately 32%) contains a 5 bp insertion (type-2). Other mutations (non-type 1 or type 2) are seen in a small minority of cases. CALR mutations in PMF tend to be associated with a favorable prognosis compared to JAK2^V617F mutations, whereas primary myelofibrosis negative for CALR, JAK2^V617F and MPL mutations (so-called triple negative) is associated with a poor prognosis and shorter survival.

The detection of a CALR gene mutation aids in the specific diagnosis of a myeloproliferative neoplasm and helps distinguish this clonal disease from a benign reactive process.