JCI Insight (Sep 2020)

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

Journal volume & issue
Vol. 5, no. 18

Abstract

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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.

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