Molecular mechanisms of bleeding disorderassociated GFI1BQ287* mutation and its affected pathways in megakaryocytes and platelets

Rinske van Oorschot, Marten Hansen, Johanna M. Koornneef, Anna E. Marneth, Saskia M. Bergevoet, Maaike G. J. M. van Bergen, Floris P. J. van Alphen, Carmen van der Zwaan, Joost H. A. Martens, Michiel Vermeulen, Pascal W. T. C. Jansen, Marijke P. A. Baltissen, Britta A. P. Laros-van Gorkom, Hans Janssen, Joop H. Jansen, Marieke von Lindern, Alexander B. Meijer, Emile van den Akker, Bert A. van der Reijden

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1460-1472
Number of pages13
JournalHaematologica
Volume104
Issue number7
DOIs
Publication statusPublished - 2019

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