TY - JOUR
T1 - Molecular mechanisms of bleeding disorderassociated GFI1BQ287* mutation and its affected pathways in megakaryocytes and platelets
AU - van Oorschot, Rinske
AU - Hansen, Marten
AU - Koornneef, Johanna M.
AU - Marneth, Anna E.
AU - Bergevoet, Saskia M.
AU - van Bergen, Maaike G. J. M.
AU - van Alphen, Floris P. J.
AU - van der Zwaan, Carmen
AU - Martens, Joost H. A.
AU - Vermeulen, Michiel
AU - Jansen, Pascal W. T. C.
AU - Baltissen, Marijke P. A.
AU - Gorkom, Britta A. P. Laros-van
AU - Janssen, Hans
AU - Jansen, Joop H.
AU - von Lindern, Marieke
AU - Meijer, Alexander B.
AU - van den Akker, Emile
AU - van der Reijden, Bert A.
N1 - Funding Information: The authors would like to thank Clemens Mellink and Anne- Marie van der Kevie-Kersemaekers from the Academic Medical Center Amsterdam, Department of Clinical Genetics, Amsterdam, the Netherlands for performing the karyotyping of BEL-5-Cl2 and Konnie M. Hebeda from the Department of Pathology, Radboudumc, Nijmegen, the Netherlands for her expert opinion on the megakaryocyte electron microscopy results. This work was supported by the Landsteiner Foundation for Blood Transfusion Research (project 1531), Sanquin PPOC 15- 25p-2089 and the Radboudumc. Funding Information: The authors would like to thank Clemens Mellink and Anne-Marie van der Kevie-Kersemaekers from the Academic Medical Center Amsterdam, Department of Clinical Genetics, Amsterdam, the Netherlands for performing the karyotyping of BEL-5-Cl2 and Konnie M. Hebeda from the Department of Pathology, Radboudumc, Nijmegen, the Netherlands for her expert opinion on the megakaryocyte electron microscopy results. This work was supported by the Landsteiner Foundation for Blood Transfusion Research (project 1531), Sanquin PPOC 15-25p-2089 and the Radboudumc. Publisher Copyright: © 2019 Ferrata Storti Foundation.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85069196894&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30655368
U2 - https://doi.org/10.3324/haematol.2018.194555
DO - https://doi.org/10.3324/haematol.2018.194555
M3 - Article
C2 - 30655368
SN - 0390-6078
VL - 104
SP - 1460
EP - 1472
JO - Haematologica
JF - Haematologica
IS - 7
ER -