Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation

Dominique Bluteau, Alessandra Balduini, Nathalie Balayn, Manuela Currao, Paquita Nurden, Caroline Deswarte, Guy Leverger, Patrizia Noris, Silverio Perrotta, Eric Solary, William Vainchenker, Najet Debili, Remi Favier, Hana Raslova

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)580-591
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number2
DOIs
Publication statusPublished - Feb 3 2014

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Ankyrin Repeat
Nucleic Acid Regulatory Sequences
Thrombocytopenia
Proto-Oncogene Protein c-fli-1
5' Untranslated Regions
Mutation
Core Binding Factor Alpha 2 Subunit
Healthy Volunteers
Leukemia
Thrombopoietin
Megakaryocytes
Oncogenes
Point Mutation
Blood Platelets
Viruses
Thrombocytopenia chromosome breakage

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bluteau, D., Balduini, A., Balayn, N., Currao, M., Nurden, P., Deswarte, C., ... Raslova, H. (2014). Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. Journal of Clinical Investigation, 124(2), 580-591. https://doi.org/10.1172/JCI71861

Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. / Bluteau, Dominique; Balduini, Alessandra; Balayn, Nathalie; Currao, Manuela; Nurden, Paquita; Deswarte, Caroline; Leverger, Guy; Noris, Patrizia; Perrotta, Silverio; Solary, Eric; Vainchenker, William; Debili, Najet; Favier, Remi; Raslova, Hana.

In: Journal of Clinical Investigation, Vol. 124, No. 2, 03.02.2014, p. 580-591.

Research output: Contribution to journalArticle

Bluteau, D, Balduini, A, Balayn, N, Currao, M, Nurden, P, Deswarte, C, Leverger, G, Noris, P, Perrotta, S, Solary, E, Vainchenker, W, Debili, N, Favier, R & Raslova, H 2014, 'Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation', Journal of Clinical Investigation, vol. 124, no. 2, pp. 580-591. https://doi.org/10.1172/JCI71861
Bluteau, Dominique ; Balduini, Alessandra ; Balayn, Nathalie ; Currao, Manuela ; Nurden, Paquita ; Deswarte, Caroline ; Leverger, Guy ; Noris, Patrizia ; Perrotta, Silverio ; Solary, Eric ; Vainchenker, William ; Debili, Najet ; Favier, Remi ; Raslova, Hana. / Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 2. pp. 580-591.
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