Work

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

Year: 2020

Type: article

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.

Source: JCI Insight

DOI: 10.1172/jci.insight.140332

Authors: 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

Institutions: University of Colorado Anschutz, Wayne State University, Children's Hospital of Michigan, Children's Mercy Hospital, Washington University in St. Louis, University of Utah, Emory University, University of Oklahoma Health Sciences Center

Language: English

Topic: Platelet Disorders and Treatments

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,100

Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke

Awards: Rocky Mountain Neurological Disorders Core Center, G1660312822, G1664773227, G2262382865, The Role of ESE-1 in HER2-Positive Breast Cancer, G4624585303, Medical Scientist Training Program, Neuronal Transdifferention in vivo: Mechanism and Potential, A SYSTEMS BIOLOGY APPROACH TO IDENTIFYING THE MECHANISMS OF SEX HORMONE INDUCED THROMBOEMBOLISM IN PRE-MENOPAUSAL WOMEN, G772292690, Predoctoral Training Program in Molecular Biology, G9000158259, G946227659

OpenAlex ID: W3080260203

FWCI: 2.023

Cites: 64

Cited by: 27

Related to: 10