Homozygous Calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency

Abstract

The pathogenesis of acquired myeloperoxidase (MPO) deficiency, a rare phenomenon observed in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), is unknown. MPO is a glycoprotein chaperoned by Calreticulin (CALR) in the endoplasmic reticulum. Mutations inCALRare frequently found in patients with myelofibrosis (MF) and essential thrombocythemia (ET) with nonmutatedJanuskinase 2(JAK2). We hypothesized that acquired MPO deficiency in MPN could be associated with the presence ofCALRmutations. A cohort of 317 MPN patients (142 polycythemia vera (PV), 94 ET and 81 MF) was screened for MPO deficiency. MPO deficiency was observed in 6/81 MF patients (7.4%), but not in PV or ET patients. Susceptibility to infections had been documented in 2/6 (33%) MPO deficient patients. Five out of six patients with MPO deficiency carried a homozygousCALRmutation and were also deficient in eosinophilic peroxidase (EPX). In contrast, one MF patient with aJAK2-V617F mutation and MPO deficiency carried two previously reportedMPOmutations and showed normal EPX activity. Patients with homozygousCALRmutations had reduced MPO protein, but normalMPOmRNA levels supporting a post-transcriptional defect in MPO production. Finally, we demonstrate in vitro that in the absence of CALR immature MPO protein precursors are degraded in the proteasome. Therefore, four decades after the first description of acquired MPO deficiency in MPN we provide the molecular correlate associated with this phenomenon and evidence thatCALRmutations can affect the biosynthesis of glycoproteins