# Unexpected mechanism underlying mislocalization of thrombocytopenia-associated ETV6 point mutation

> **NIH NIH F30** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $40,048

## Abstract

PROJECT SUMMARY/ABSTRACT
ETV6 is a transcriptional repressor involved inhematopoietic stem cell maintenance and terminal differentiation
of megakaryocytes. ETV6 conditional knockout mice demonstrate a marked decrease in peripheral platelet
counts and a compensatory increase in immature megakaryocytes. In concordance with these findings, in
recent years, a number of germline mutations in ETV6 that result in mislocalization of the protein from the
nucleus to the cytoplasm have been associated with inherited thrombocytopenia. Carriers of these mutations
are also at an increased risk of hematologic malignancies as ~30% have gone on to develop myelodysplastic
syndrome or leukemia. Most of these germline mutations are found in the DNA-binding domain (DBD) of ETV6.
Functional studies of these DBD mutations demonstrate a loss of DNA-binding capacity in vitro and a loss of
transcriptional repression in cells. However, one mutation, the Pro214Leu missense mutation identified in 5
families thus far, occurs in the long intrinsically disordered central domain of ETV6. It too demonstrates a loss
of transcriptional repression in vitro, but the mechanism explaining this loss has not yet been established.
Preliminary data I have gathered demonstrates that this Pro214Leu missense mutation creates a de novo
nuclear export signal (NES) leading to exportin 1 (XPO1) mediated nuclear export. This constitutes the first
described instance of a point mutation creating a de novo NES. We intend to develop cellular and animal
model systems to probe the effects of this unexpected disease mechanism on thrombopoiesis. We are
developing a homologous ETV6 P214L transgenic mouse line will validate its suitability as an animal model of
ETV6-related thrombocytopenia. This will allow us to use genetic and chemical tools to study the effects of
ETV6 P214L nuclear relocalization on megakaryocyte and platelet development. Lastly, a preliminary
bioinformatics search utilizing ClinVar, a publicly available database of genetic variation, and an NES
prediction server has yielded additional candidate mutations that may also create de novo NESs. We intend to
show that missense mutation dependent nuclear export is a general mechanism of disease, and
characterization of candidate NESs may yield novel biomarkers of disease.

## Key facts

- **NIH application ID:** 10883548
- **Project number:** 5F30HL167629-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Michael R McConville
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,048
- **Award type:** 5
- **Project period:** 2023-01-31 → 2026-01-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883548

## Citation

> US National Institutes of Health, RePORTER application 10883548, Unexpected mechanism underlying mislocalization of thrombocytopenia-associated ETV6 point mutation (5F30HL167629-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10883548. Licensed CC0.

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