Molecular mechanisms underlying the megakaryocyte developmental defects caused by the ETV6 p.R369W variant

In this study, we explored the function of the transcription factor ETV6 in megakaryopoiesis and assessed the impact of the pathogenic variant ETV6 p.R369W on megakaryocyte and platelet development. We hypothesized that ETV6 p.R369W acts in a dominant-negative manner, mimicking the molecular consequences of ETV6 deficiency. To investigate this, we overexpressed both wild-type ETV6 and the ETV6 p.R369W variant in Meg01 cells. Transcriptomic analysis revealed that ETV6 p.R369W upregulated genes associated with hematopoietic progenitor states and platelet activation, closely resembling the gene expression changes observed in ETV6 knockout cells.