Searching for CALRity in myeloproliferative neoplasms.

Abstract

Ten years ago, the discovery of JAK2 mutations in BCR/ABL1 -negative myeloproliferative neoplasms (MPNs) revolutionized our understanding of these challenging disorders.1,2 Testing for the JAK2 V617F point mutation, found in more than 95% of cases of polycythemia vera (PV) and approximately 50% of cases of essential thrombocytosis (ET) and primary myelofibrosis (PMF), quickly became part of the standard-of-care evaluation of unexplained leukocytosis or thrombocytosis. Subsequent work demonstrated that the rare cases of PV lacking the JAK2 V617F mutation contain other mutations in exons 12 to 14 of JAK2 , while approximately 5% to 15% of cases of ET and PMF without the JAK2 V617F mutation contain mutations in exon 10 of MPL , the thrombopoietin receptor.1,2 Until recently, however, most JAK2 V617F–negative MPNs had no known molecular abnormality that could provide pathologists with objective evidence of a neoplasm and assist in differentiating MPNs from reactive processes. In late 2013, a major piece of the remaining puzzle was solved with the discovery that most MPNs lacking JAK2 V617F or MPL mutations carry mutations in CALR , the gene encoding the endoplasmic reticulum chaperone protein, calreticulin.3,4 These mutations consist of a variety of insertions and deletions in exon 9 of CALR . The so-called type 1 mutation (~50% of mutations) is caused by a 52–base pair (bp) deletion, the type 2 mutation (~30% of mutations) is due to a 5-bp insertion, and the remaining mutations consist of other variably sized insertions and deletions. Interestingly, all CALR mutations appear to be similar in that they result in a frameshift with production of an identical 36–amino acid C-terminus and deletion of the KDEL sequence, which normally retains the wild-type calreticulin protein within the endoplasmic reticulum. Over the past year, numerous groups have examined the incidence …