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

Marlie H. Fisher, Gregory D. Kirkpatrick, Brett Stevens, Courtney Jones, Michael Callaghan, Madhvi Rajpurkar, Joy Fulbright, Megan A. Cooper, Jesse Rowley, Christopher C. Porter, Arthur Gutierrez-Hartmann, Kenneth Jones, Craig Jordan, Eric M. Pietras, Jorge Di Paola

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere140332
JournalJCI Insight
Volume5
Issue number18
DOIs
StatePublished - Aug 2020

Fingerprint Dive into the research topics of 'ETV6 germline mutations cause HDAC3/ NCOR2 mislocalization and upregulation of interferon response genes'. Together they form a unique fingerprint.

Cite this