ETV6 germline mutations cause HDAC3/NCOR2 mislocalization and upregulation of interferon response genes

• Published in: JCI insight Vol. 5; no. 18
• Main Authors: Fisher, Marlie H, Kirkpatrick, Gregory D, Stevens, Brett, Jones, Courtney, Callaghan, Michael, Rajpurkar, Madhvi, Fulbright, Joy, Cooper, Megan A, Rowley, Jesse, Porter, Christopher C, Gutierrez-Hartmann, Arthur, Jones, Kenneth, Jordan, Craig, Pietras, Eric M, Di Paola, Jorge
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 17-09-2020; American Society for Clinical investigation
• Subjects: Bone Marrow Diseases - etiology; Bone Marrow Diseases - metabolism; Bone Marrow Diseases - pathology; Child; Cohort Studies; ETS Translocation Variant 6 Protein; Genetic Predisposition to Disease; Germ-Line Mutation; Hematology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Megakaryocytes - metabolism; Megakaryocytes - pathology; Nuclear Receptor Co-Repressor 2 - genetics; Nuclear Receptor Co-Repressor 2 - metabolism; Protein Transport; Proto-Oncogene Proteins c-ets - genetics; Repressor Proteins - genetics; Thrombocytopenia - etiology; Thrombocytopenia - metabolism; Thrombocytopenia - pathology; Hematology; Transcription
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.140332

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.