Capaci Valeria, Zanchetta Melania Eva, Fontana Giorgia, Ammeti Daniele, Bottega Roberta, Faleschini Michela, Savoia Anna
Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, Italy.
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy.
Cells. 2024 Dec 30;14(1):23. doi: 10.3390/cells14010023.
Mutations in the genes , , and cause three clinically overlapping thrombocytopenias characterized by a predisposition to hematological neoplasms. The gene, which encodes a protein involved in protein-protein interactions, is downregulated by RUNX1 during megakaryopoiesis. Mutations in 5'UTR of ANKRD26, leading to ANKRD26-RT, disrupt this regulation, resulting in the persistent expression of ANKRD26, which leads to impaired platelet biogenesis and an increased risk of leukemia. Although ANKRD26 and ETV6 exhibit inverse expression during megakaryopoiesis, ETV6 does not regulate the ANKRD26 expression. Hypothesizing an interplay between ETV6 and ANKRD26 through in vitro studies, we explored the interactions between the two proteins. In this study, we found that ANKRD26 interacts with ETV6 and retains it in the cytoplasm, phenocopying ETV6-RT-related mutants. We found that GPS2, a component of the NCoR complex, binds both ANKRD26 and ETV6, mediating this interaction. Furthermore, ANKRD26 overexpression deregulates ETV6 transcriptional repression, supporting a common pathogenic mechanism underlying ANKRD26-RT, FPD/AML, and ETV6-RT. Our results unveil a novel ANKRD26-ETV6-GPS2 axis, providing new insights to investigate the molecular mechanism underlying thrombocytopenias with a predisposition to myeloid neoplasms that need to be further characterized.
基因、和的突变会导致三种临床症状重叠的血小板减少症，其特征是易患血液系统肿瘤。ANKRD26基因编码一种参与蛋白质-蛋白质相互作用的蛋白质，在巨核细胞生成过程中受RUNX1下调。ANKRD26 5'UTR的突变导致ANKRD26-RT，破坏了这种调节，导致ANKRD26持续表达，进而导致血小板生成受损和白血病风险增加。尽管ANKRD26和ETV6在巨核细胞生成过程中表达呈负相关，但ETV6并不调节ANKRD26的表达。通过体外研究推测ETV6和ANKRD26之间存在相互作用，我们探索了这两种蛋白质之间的相互作用。在本研究中，我们发现ANKRD26与ETV6相互作用并将其保留在细胞质中，模拟了ETV6-RT相关突变体的表型。我们发现NCoR复合物的一个组成部分GPS2同时结合ANKRD26和ETV6，介导了这种相互作用。此外，ANKRD26的过表达解除了ETV6的转录抑制，支持了ANKRD26-RT、FPD/AML和ETV6-RT共同的致病机制。我们的结果揭示了一个新的ANKRD26-ETV6-GPS2轴，为研究易患髓系肿瘤的血小板减少症的分子机制提供了新的见解，这需要进一步表征。
