From development to disease:Cellular models of hematopoiesis and platelet disorders

作者：Haitao Zhang · 发表于：EUR Research Repository (Erasmus University Rotterdam) · 年份：2026 · 研究领域：Platelet Disorders and Treatments、Blood disorders and treatments、Williams Syndrome Research

This thesis explores the transcriptional regulation of hematopoiesis, with a focus on megakaryocyte (MK) and platelet development. Many transcription factors (TFs), such as GFI1B, FLI1, and ETV6, are expressed in both hematopoietic stem cells (HSCs) and MKs, consistent with the notion that MKs may derive directly from HSCs. Germline mutations in these TFs are associated with inherited platelet disorders; however, the mechanisms by which specific variants disrupt gene regulation and cellular function remain largely unresolved. Studying individual TF mutants offers a powerful entry point to unravel the downstream consequences of disrupted transcriptional control. Because many of these mutations do not cause complete loss of function, but rather result in dominant-negative effects, their impact cannot be predicted based on sequence alone. By modeling specific variants such as FLI1 p.Met100* or ETV6 p.R369W in hematopoietic cell systems, we can dissect how these mutants alter gene expression profiles, protein interactions, and cellular phenotypes. This not only improves our understanding of disease mechanisms but also informs functional classification of variants of uncertain significance (VUS), which are frequently encountered in clinical genetic testing. Moreover, transcriptional profiling of these mutants can reveal key gene networks and regulatory circuits affected in disease, offering potential biomarkers or therapeutic targets. As such, functional studies of TF mutants brid...