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Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX 1 targets
Author(s) -
Glembotsky A. C.,
Bluteau D.,
Espasandin Y. R.,
Goette N. P.,
Marta R. F.,
Marin Oyarzun C. P.,
Korin L.,
Lev P. R.,
Laguens R. P.,
Molinas F. C.,
Raslova H.,
Heller P. G.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12550
Subject(s) - platelet disorder , runx1 , platelet , platelet activation , platelet glycoprotein gpiib iiia complex , cancer research , biology , immunology , microbiology and biotechnology , transcription factor , genetics , gene
Summary Background Familial platelet disorder with a predisposition to acute myelogenous leukemia ( FPD / AML ) is an inherited platelet disorder caused by a germline RUNX 1 mutation and characterized by thrombocytopenia, a platelet function defect, and leukemia predisposition. The mechanisms underlying FPD / AML platelet dysfunction remain incompletely clarified. We aimed to determine the contribution of platelet structural abnormalities and defective activation pathways to the platelet phenotype. In addition, by using a candidate gene approach, we sought to identify potential RUNX 1‐regulated genes involved in these defects. Methods Lumiaggregometry, α‐granule and dense granule content and release, platelet ultrastructure, α IIb β 3 integrin activation and outside‐in signaling were assessed in members of one FPD / AML pedigree. Expression levels of candidate genes were measured and luciferase reporter assays and chromatin immunoprecipitation were performed to study NF ‐E2 regulation by RUNX 1. Results A severe decrease in platelet aggregation, defective α IIb β 3 integrin activation and combined αδ storage pool deficiency were found. However, whereas the number of dense granules was markedly reduced, α‐granule content was heterogeneous. A trend towards decreased platelet spreading was found, and β 3 integrin phosphorylation was impaired, reflecting altered outside‐in signaling. A decrease in the level of transcription factor p45 NF ‐E2 was shown in platelet RNA and lysates, and other deregulated genes included RAB 27B and MYL 9 . RUNX 1 was shown to bind to the NF ‐E2 promoter in primary megakaryocytes, and wild‐type RUNX 1, but not FPD / AML mutants, was able to activate NF ‐E2 expression. Conclusions The FPD / AML platelet function defect represents a complex trait, and RUNX 1 orchestrates platelet function by regulating diverse aspects of this process. This study highlights the RUNX 1 target NF ‐E2 as part of the molecular network by which RUNX 1 regulates platelet biogenesis and function.