title: Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation.
abstract: Point mutations in the 5' UTR of ankyrin repeat domain 26 (ANKRD26) are associated with familial thrombocytopenia 2 (THC2) and a predisposition to leukemia. Here, we identified underlying mechanisms of ANKRD26-associated thrombocytopenia. Using megakaryocytes (MK) isolated from THC2 patients and healthy subjects, we demonstrated that THC2-associated mutations in the 5' UTR of ANKRD26 resulted in loss of runt-related transcription factor 1 (RUNX1) and friend leukemia integration 1 transcription factor (FLI1) binding. RUNX1 and FLI1 binding at the 5' UTR from healthy subjects led to ANKRD26 silencing during the late stages of megakaryopoiesis and blood platelet development. We showed that persistent ANKRD26 expression in isolated MKs increased signaling via the thrombopoietin/myeloproliferative leukemia virus oncogene (MPL) pathway and impaired proplatelet formation by MKs. Importantly, we demonstrated that ERK inhibition completely rescued the in vitro proplatelet formation defect. Our data identify a mechanism for development of the familial thrombocytopenia THC2 that is related to abnormal MAPK signaling.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bluteau
authors.forename: Alessandra
authors.initials: A
authors.lastname: Balduini
authors.forename: Nathalie
authors.initials: N
authors.lastname: Balayn
authors.forename: Manuela
authors.initials: M
authors.lastname: Currao
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.forename: Caroline
authors.initials: C
authors.lastname: Deswarte
authors.forename: Guy
authors.initials: G
authors.lastname: Leverger
authors.forename: Patrizia
authors.initials: P
authors.lastname: Noris
authors.forename: Silverio
authors.initials: S
authors.lastname: Perrotta
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: Remi
authors.initials: R
authors.lastname: Favier
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D019457:Chromosome Breakage; D025063:Chromosome Disorders / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008297:Male; D008533:Megakaryocytes / Q000166:cytology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000378:metabolism; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000151:congenital* / Q000235:genetics; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; C583630:ANKRD26 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C078433:FLI1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D051789:Proto-Oncogene Protein c-fli-1; C493728:RUNX1 protein, human; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human