title: 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 (MPNs), is unknown. MPO is a glycoprotein (GP) chaperoned by calreticulin (CALR) in the endoplasmic reticulum. Mutations in CALR are frequently found in patients with myelofibrosis (MF) and essential thrombocythemia (ET) with nonmutated Janus kinase 2 (JAK2). We hypothesized that acquired MPO deficiency in MPN could be associated with the presence of CALR mutations. A cohort of 317 patients with MPN (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 6 patients with MPO deficiency carried a homozygous CALR mutation and were also deficient in eosinophilic peroxidase (EPX). In contrast, 1 patient with MF, a JAK2-V617F mutation, and MPO deficiency, carried 2 previously reported MPO mutations and showed normal EPX activity. Patients with homozygous CALR mutations had reduced MPO protein, but normal MPO messenger RNA (mRNA) levels supporting a posttranscriptional 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, 4 decades after the first description of acquired MPO deficiency in MPN, we provide the molecular correlate associated with this phenomenon and evidence that CALR mutations can affect the biosynthesis of GPs.
authors.affiliation: Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland;
authors.forename: Alexandre P A
authors.identifier: 0000-0002-1535-8692
authors.initials: AP
authors.lastname: Theocharides
authors.affiliation: Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland; and.
authors.forename: Pontus
authors.initials: P
authors.lastname: Lundberg
authors.affiliation: Institute of Neuropathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Asvin K K
authors.initials: AK
authors.lastname: Lakkaraju
authors.affiliation: Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland;
authors.forename: Veronika
authors.initials: V
authors.lastname: Lysenko
authors.affiliation: Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland;
authors.forename: Renier
authors.initials: R
authors.lastname: Myburgh
authors.affiliation: Institute of Neuropathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.affiliation: Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland; and.
authors.forename: Radek C
authors.initials: RC
authors.lastname: Skoda
authors.affiliation: Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland;
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
mesh_terms: D000818:Animals; D037282:Calreticulin / Q000235:genetics*; D002478:Cells, Cultured; D015331:Cohort Studies; D006720:Homozygote; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis
chemical_list: C576483:CALR protein, human; D037282:Calreticulin; D009195:Peroxidase; D046988:Proteasome Endopeptidase Complex