Abstract

In his landmark perspective written in 1951, William Dameshek fi rst characterized “ myeloproliferative disorders ” ( “ MPDs ” ) as a related group of diseases, alluding to the presence of a shared “ myelostimulatory factor ” accounting for overlapping clinical and laboratory features [1]. Nearly 55 years after this speculation, the JAK2 V617F mutation was discovered in patients with essential thrombocythemia (ET), polycythemia vera (PV) and myelofi brosis (MF) [2 – 5]. Shortly thereafter, mutations of the thrombopoeitin receptor MPL were reported in a minority of patients with ET and MF [6]. Th e discovery of these driver mutations contributed greatly to the understanding of the myeloproliferative neoplasm (MPN) phenotype and pathogenesis, enhanced diagnostic capability and led to the development of novel therapeutics; consequently, Dameshek ’ s original “ MPDs ” were reclassifi ed as neoplasms, or “ MPNs. ” However, as many as 40% of patients with ET and MF remained molecularly undefi ned by a driver mutation until late 2013, when the fi rst reports of calreticulin ( CALR ) gene mutations in JAK2/MPL -negative patients were published, representing Dameshek ’ s third myelostimulatory factor in the MPN [7,8]. In less than 1 year from this discovery, there is accumulating evidence suggesting distinctions in clinical phenotype and prognosis in patients with CALR -mutated ET and MF. In one of the early reports, Klampfl et al . reported CALR mutations in 67% and 88% of patients with JAK2/ MPL -negative ET and MF, respectively [7]. Type 1 (52 bp deletion; c.1092_1143del) and type 2 (5 bp insertion; c.1154_1155insTTGTC) mutations accounted for the majority of cases, but the former were more common in MF, compared to ET. Regarding clinical phenotype, when compared to patients with JAK2- mutated disease, patients with CALR mutated ET and MF had a lower leukocyte count and a higher platelet count (patients with CALR -mutated ET also had a lower hemoglobin [Hgb] level compared to patients with JAK2 -positive ET). In a companion publication, Nangalia et al . reported CALR mutations in 26 of 31 (84%) JAK2/MPL negative samples that underwent whole exome sequencing; in a follow-up cohort, 71% and 56% of patients with JAK2 V617F/MPL -negative ET and MF had CALR mutations [8]. Similarly, patients with CALR -mutated disease had lower Hgb levels and higher platelet counts compared to patients with JAK2 -mutated disease. In two large studies of patients with ET [9,10], similar blood count associations were noted, but one report associated CALR with younger age [10] and a second with male gender [9], complementing observations of gender-diff erences in MPN [11,12].

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.