Molecular mechanisms of bleeding disorderassociated GFI1BQ287* mutation and its affected pathways in megakaryocytes and platelets
| العنوان: | Molecular mechanisms of bleeding disorderassociated GFI1BQ287* mutation and its affected pathways in megakaryocytes and platelets |
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| المؤلفون: | van Oorschot, Rinske, Hansen, Marten, Koornneef, Johanna M, Marneth, Anna E, Bergevoet, Saskia M, van Bergen, Maaike G J M, van Alphen, Floris P J, van der Zwaan, Carmen, Martens, Joost H A, Vermeulen, Michiel, Jansen, Pascal W T C, Baltissen, Marijke P A, Gorkom, Britta A P Laros-van, Janssen, Hans, Jansen, Joop H, von Lindern, Marieke, Meijer, Alexander B, van den Akker, Emile, van der Reijden, Bert A, Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics |
| المساهمون: | Academic Medical Center, AII - Inflammatory diseases, Landsteiner Laboratory, Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics |
| المصدر: | Haematologica, 104(7), 1460-1472. Ferrata Storti Foundation Haematologica, 104, 1460-1472 Haematologica, 104(7), 1460. Ferrata Storti Foundation Haematologica, 104, 7, pp. 1460-1472 |
| بيانات النشر: | Ferrata Storti Foundation (Haematologica), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Proteomics and Chromatin Biology, Megakaryocyte differentiation, Cellular differentiation, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Hematology, Biology, Cell biology, RCOR1, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Megakaryocyte, medicine, Platelet, Histone deacetylase, Induced pluripotent stem cell, Molecular Biology, 030215 immunology, Megakaryopoiesis |
| الوصف: | Dominant-negative mutations in the transcription factor Growth Factor Independence-1B (GFI1B), such as GFI1BQ287*, cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that both normal and Q287* mutant GFI1B interacted most strongly with the lysine specific demethylase-1 - REST corepressor - histone deacetylase (LSD1-RCOR-HDAC) complex in megakaryoblasts. Sequestration of this complex by GFI1BQ287* and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1BQ287*-induced pluripotent stem cells also phenocopied abnormalities seen in patients. Proteome studies on normal and mutant-induced pluripotent stem cell-derived megakaryocytes identified a multitude of deregulated pathways downstream of GFI1BQ287* including cell division and interferon signaling. Proteome studies on platelets from GFI1BQ287* patients showed reduced expression of proteins implicated in platelet function, and elevated expression of proteins normally downregulated during megakaryocyte differentiation. Thus, GFI1B and LSD1 regulate a broad developmental program during megakaryopoiesis, and GFI1BQ287* deregulates this program through LSD1-RCOR-HDAC sequestering. |
| وصف الملف: | application/pdf; image/pdf |
| تدمد: | 1592-8721 0390-6078 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7bb1b24d0699c08b3ca5750d613aef3cTest https://doi.org/10.3324/haematol.2018.194555Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7bb1b24d0699c08b3ca5750d613aef3c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15928721 03906078 |
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