ETV6 germline mutations cause HDAC3/NCOR2 mislocalization and upregulation of interferon response genes
Marlie H. Fisher, Gregory D. Kirkpatrick, Brett M. Stevens, Courtney L. Jones, Michael U. Callaghan, Madhvi Rajpurkar, Joy M. Fulbright, Megan A. Cooper, Jesse W. Rowley, Christopher C. Porter, Arthur Gutierrez‐Hartmann, Kenneth L. Jones, Craig T. Jordan, Eric M. Pietras, Jorge Di Paola
Abstract
ETV6 is an ETS family transcription factor that plays a key role in hematopoiesis and megakaryocyte development. Our group and others have identified germline mutations in ETV6 resulting in autosomal dominant thrombocytopenia and predisposition to malignancy; however, molecular mechanisms defining the role of ETV6 in megakaryocyte development have not been well established. Using a combination of molecular, biochemical, and sequencing approaches in patient-derived PBMCs, we demonstrate abnormal cytoplasmic localization of ETV6 and the HDAC3/NCOR2 repressor complex that led to overexpression of HDAC3-regulated interferon response genes. This transcriptional dysregulation was also reflected in patient-derived platelet transcripts and drove aberrant proplatelet formation in megakaryocytes. Our results suggest that aberrant transcription may predispose patients with ETV6 mutations to bone marrow inflammation, dysplasia, and megakaryocyte dysfunction.