- Novel regulators of megakaryopoiesis: The road less traveled by
C.E. van der Schoot
- Award date
- 26 May 2015
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Platelet transfusions are given to patients with low platelet counts due to, for example, chemotherapy. Currently, research is done to produce platelets in culture systems. Although researchers are successful in producing platelets, the yield of these systems is still inefficient due to our limited knowledge about the differentiation of hematopoietic stem cells into megakaryocytes, the platelet precursors.
We identified the transcription factor MEIS1 to be specific for megakaryocytes when the transcriptomes of differentiated adult blood cells was compared. Given the exclusive expression in megakaryocytes, we therefore investigated the contribution of MEIS1 and several MEIS1 targets to megakaryopoiesis. We show that MEIS1 specifies hematopoietic progenitor cells to become megakaryocytes by enforcing expression of lineage specific genes and inhibiting granulocytic gene expression. Next, the role of two MEIS1 targets, ATXN2 and TPM1, was studied. Our results show that the RNA binding protein ATXN2 controls protein synthesis during early megakaryopoiesis which directly impacts on platelet reactivity. We thus provide first evidence for the importance of controlled protein synthesis in megakaryopoiesis. Furthermore, researchers have been debating the relevance of actin during megakaryopoiesis. When analyzing the role of the actin-binding protein TPM1, we could show that TPM1 controls proper actin localization and polymerization during early and late events of megakaryopoiesis, clearly underlining the importance of actin in these processes.
In the context of current platelet culture systems, our resultsmay contribute to more efficient megakaryocytic lineage commitment and thus the theoretic yield of platelets, as well as to higher quality of the produced platelets.
- Research conducted at: Sanquin Research an Landsteiner Laboratory, AMC
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