Calreticulin (CALR) Mutation Screen in Myeloproliferative Neoplasms (MPNs)

Somatic JAK2 V617F mutation is present in a majority (95%) of patients with Polycythaemia Vera (PV), but only in 50-60% of patients with Es-sential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). Muta-tions in the gene encoding thrombopoietin receptor (MPL) exist in a small subset (5-10%) of patients with JAK2 V617F negative ET and PMF.

Recently, recurrent mutations in the gene encoding calreticulin (CALR) have been identified in a majority (70-85%) of MPN patients without JAK2 or MPL mutations. CALR mutations are never seen in PV and are always mutually exclusive to JAK2 and MPL mutations. These heterozygous mutations (insertions or deletions), located in exon 9, lead to a frameshift to a specific altered reading frame and result in a mutant protein with a novel C-terminal. ET and PMF patients with CALR mutations have lower haemoglobins, higher platelet counts, lower risk of thrombosis and a better overall survival than patients with mutated JAK2.

The causal relationship between CALR mutations and excessive platelet production is further supported by identification of these mutations in a proportion of RARS-T patients but not in MDS, AML or CML. Thus, CALR mutations are the second most frequent mutation after JAK2 in MPN’s and impart a more indolent phenotype. CALR mutations are major driver events in the pathogenesis of MPN, occurring at the stem cell level and remain stable during disease evolution.

We suggest sequential testing on peripheral blood in order of mutation frequency for 1) JAK2, 2) CALR and 3) MPL, thereby improving the diagnostic accuracy of myeloproliferative neoplasms in the same way JAK2 testing has in the last decade.