TY - JOUR
T1 - ETV6 germline mutations cause HDAC3/ NCOR2 mislocalization and upregulation of interferon response genes
AU - Fisher, Marlie H.
AU - Kirkpatrick, Gregory D.
AU - Stevens, Brett
AU - Jones, Courtney
AU - Callaghan, Michael
AU - Rajpurkar, Madhvi
AU - Fulbright, Joy
AU - Cooper, Megan A.
AU - Rowley, Jesse
AU - Porter, Christopher C.
AU - Gutierrez-Hartmann, Arthur
AU - Jones, Kenneth
AU - Jordan, Craig
AU - Pietras, Eric M.
AU - Di Paola, Jorge
N1 - Funding Information:
We would like to thank the families we studied for their contribution to this project, the sample repository supported by the Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Children’s Hospital and the Center for Pediatric Immunology at St. Louis Children’s Hospital, and Bruce Kirkpatrick for visualizations. This work was supported by US NIH grants: R01 HL120728 and R01 HL141794 (to JDP), R01 CA141201 (to AGH), 5T32GM008730-19 (University of Colorado Molecular Biology Program), and 5T32GM008497-23 (University of Colorado Medical Scientist Training Program).
Publisher Copyright:
Copyright: © 2020, Fisher et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85091191814&partnerID=8YFLogxK
U2 - 10.1172/JCI.INSIGHT.140332
DO - 10.1172/JCI.INSIGHT.140332
M3 - Article
C2 - 32841218
AN - SCOPUS:85091191814
SN - 2379-3708
VL - 5
JO - JCI insight
JF - JCI insight
IS - 18
M1 - e140332
ER -