title: Ubiquitin/proteasome-rich particulate cytoplasmic structures (PaCSs) in the platelets and megakaryocytes of ANKRD26-related thrombo-cytopenia.
abstract: ANKRD26-related thrombocytopenia (ANKRD26-RT) is an autosomal-dominant thrombocytopenia caused by mutations in the 5'UTR of the ANKRD26 gene.  ANKRD26-RT is characterised by dysmegakaryopoiesis and an increased risk of leukaemia. PaCSs are novel particulate cytoplasmic structures with selective immunoreactivity for polyubiquitinated proteins and proteasome that have been detected in a number of solid cancers, in the epithelia of  Helicobacter pylori  gastritis and related preneoplastic lesions, and in the neutrophils of Schwachman-Diamond syndrome, a genetic disease with neutropenia and increased leukaemia risk. We searched for PaCSs in blood cells from 14 consecutive patients with  ANKRD26-RT. Electron microscopy combined with immunogold staining for polyubiquitinated proteins, 20S and 19S proteasome showed PaCSs in most ANKRD26-RT platelets, as in a restricted minority of platelets from healthy controls and from subjects with other inherited or immune thrombocytopenias. In ANKRD26-RT platelets, the PaCS amount exceeded that of control platelets by a factor of 5 (p<0.0001). Immunoblotting showed that the higher PaCS number was associated with increased amounts of polyubiquitinated proteins and proteasome in ANKRD26-RT platelets. PaCSs were also extensively represented in ANKRD26-RT megakaryocytes, but not in healthy control megakaryocytes, and were absent in other ANKRD26-RT and control blood cells. Therefore, large amounts of PaCSs are a characteristic feature of ANKRD26-RT platelets and megakaryocytes, although these novel cell components are also present in a small subpopulation of normal platelets. The widespread presence of PaCSs in inherited diseases with increased leukaemia risk, as well as in solid neoplasms and their preneoplastic lesions, suggests a link of these structures with oncogenesis.
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Necchi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Balduini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Noris
authors.forename: Serena
authors.initials: S
authors.lastname: Barozzi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sommi
authors.forename: Christian
authors.initials: C
authors.lastname: di Buduo
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Balduini
authors.forename: Enrico
authors.initials: E
authors.lastname: Solcia
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pecci
mesh_terms: D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000201:enzymology* / Q000648:ultrastructure; D015153:Blotting, Western; D016022:Case-Control Studies; D022083:Cytoplasmic Structures / Q000201:enzymology* / Q000648:ultrastructure; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008533:Megakaryocytes / Q000201:enzymology* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000097:blood*; D013921:Thrombocytopenia / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054875:Ubiquitination; D055815:Young Adult
chemical_list: D046988:Proteasome Endopeptidase Complex