Functional characterization of RUNX1 variants in the context of FPDMM

Le résumé fourni par la source

Germline variants in RUNX1 cause familial platelet disorder with associated myeloid malignancies (FPDMM). The functional impact of RUNX1 missense variants is often unclear, so further investigations are needed to determine their clinical relevance. RUNX1 binds CBFβ and together they function as a transcriptional regulator. To functionally characterize 9 variants of unknown significance (VUS), we performed western blotting, FACS-FRET assay, and luciferase reporter assays with 4 independent reporters in HEK293T cells. As a proof of principle, 6 known pathogenic RUNX1 variants were investigated in parallel. In comparison with RUNX1 wild type, we showed significant functional impairment for all known pathogenic variants and gained evidence for the functional relevance of 6 RUNX1 VUS. They showed reduced ability to activate transcription of different reporters. Impaired dimerization capacity to CBFβ and/or reduced RUNX1 phosphorylation was detectable. Additionally, these RUNX1 VUS accumulated in the cells indicating altered degradation. Our results help to elucidate the clinical impact of RUNX1 VUS. In the future, additional assays will be developed to characterize VUS in more detail.

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