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Molecular mechanisms of bleeding disorderassociated GFI1B(Q287*) mutation and its affected pathways in megakaryocytes and platelets

Dominant-negative mutations in the transcription factor Growth Factor Independence-1B (GFI1B), such as GFI1B(Q287*), 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 bot...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601108/
https://www.ncbi.nlm.nih.gov/pubmed/30655368
http://dx.doi.org/10.3324/haematol.2018.194555
Descripción
Sumario:Dominant-negative mutations in the transcription factor Growth Factor Independence-1B (GFI1B), such as GFI1B(Q287*), 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 GFI1B(Q287*) and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1B(Q287*)-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 GFI1B(Q287*) including cell division and interferon signaling. Proteome studies on platelets from GFI1B(Q287*) 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 GFI1B(Q287*) deregulates this program through LSD1-RCOR-HDAC sequestering.