In Frame Calr Exon 9 Mutations: Often Ignored But Potentially Significant

Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are characterized by the overproduction of mature blood cells and variable bone marrow fibrosis. MPNs attributed to dysregulation of the Janus kinase 2 (JAK2) pathway include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Somatic mutations in JAK2, thrombopoietin receptor (MPL), and calreticulin (CALR) have been identified as driver mutations with direct or upstream upregulation of JAK2. CALR mutations are the most recently described, with the two most common mutations being a 52-base pair (bp) deletion (type 1) or 5 bp insertion (type2) in exon 9. Studies have shown a prognostic advantage to type1/type 1 like CALR driven MPNs over JAK2, MPL, and type2 CALR driven MPNs. Rarer CALR exon 9 mutations have also been identified in presumed MPN patients negative for JAK2 and MPL mutations. In these cases variable predicted changes to the CALR protein have resulted in speculative interpretations as to their relevance in the diagnosis of a suspected MPN.