Genetics and epigenetics in megakaryopoiesis: the role of GFI1B (LSBR 1531)
Project leader: Dr. Bert A. van der Reijden (RadboudUMC), Dr. Marieke von Lindern (Sanquin)
PhD student: Maaike van Bergen (Sept. 2016 – March 2021)
Technician: Tatjana Wüst (Sept. 2016 – Jan. 2018 (50%))

Inherited bleeding disorders caused by a paucity in properly functioning platelets have a negative impact on life quality and if not properly treated can be life threatening. A better understanding of the causes of bleeding disorders may eventually lead to new avenues to treat patients. Here we have investigated how inherited changes in the GFI1B gene/protein result in bleedings. Normally, GFI1B binds DNA to regulate the activity of genes pertinent to the development of blood cells that produce platelets. We observed that bleeding associated mutant GFI1B cannot bind DNA and that it quenches a large protein complex. As a consequence, this complex cannot activate genes required for platelet production. By comparing the proteins present in GFI1B mutant platelets to healthy platelets a plethora of known and new platelet proteins were shown to be significantly diminished in the former. These data provide important insights into new biological pathways important for platelet formation and maturation. Next to GFI1B, inherited bleeding disorders caused by variants in the GATA1 and RUNX1 genes were investigated. As the platelets for the three different bleeding disorders show strikingly similar abnormalities, we anticipated to find a reduction of common proteins relevant for platelet biology. Unexpectedly, we observed that the reduction of not a single protein was shared among the different disorders. This indicates that GATA1, GFI1B and RUNX1 regulate platelet development and formation in distinct manners. Additional studies are warranted to determine how variants in GATA1 and RUNX1 affect platelet biology at the molecular level to identify new therapeutic targets for these bleeding disorders.