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Title: Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors
Authors: Poggi, Marjorie ×
Canault, Matthias
Favier, Marie
Turro, Ernest
Saultier, Paul
Ghalloussi, Dorsaf
Baccini, Veronique
Vidal, Lea
Mezzapesa, Anna
Chelghoum, Nadjim
Mohand-Oumoussa, Badreddine
Falaise, Cé Line
Favier, Rémi
Ouwehand, Willem H
Fiore, Mathieu
Peiretti, Franck
Morange, Pierre Emmanuel
Saut, Noémie
Bernot, Denis
Greinacher, Andreas
Nurden, Alan T
Nurden, Paquita
Freson, Kathleen #
Trégouët, David-Alexandre #
Raslova, Hana #
Alessi, Marie-Christine #
Issue Date: Sep-2016
Publisher: Il Pensiero Scientifico
Series Title: Haematologica vol:Ahead of print
Article number: haematol.2016.147694
Abstract: Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to co-repressors. We also observed large expansion of CFU-MKs derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34+ cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton Cdc42 and RhoA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34+ cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels.
URI: 
ISSN: 0390-6078
Publication status: accepted
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
× corresponding author
# (joint) last author

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