MEIS1 regulates early erythroid and megakaryocytic cell fate

• Published in: Haematologica (Roma) 2014-10, Vol.99 (10), p.1555-1564
• Main Authors: Zeddies, Sabrina, Jansen, Sjoert B G, di Summa, Franca, Geerts, Dirk, Zwaginga, Jaap J, van der Schoot, C Ellen, von Lindern, Marieke, Thijssen-Timmer, Daphne C
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Antigens, CD34 - metabolism; Cell Differentiation - genetics; Cell Lineage - genetics; Cluster Analysis; Erythroid Cells - cytology; Erythroid Cells - metabolism; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - metabolism; Erythropoiesis - genetics; Gene Expression Profiling; Gene Expression Regulation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Megakaryocyte-Erythroid Progenitor Cells - cytology; Megakaryocyte-Erythroid Progenitor Cells - metabolism; Megakaryocytes - cytology; Megakaryocytes - metabolism; Myeloid Ecotropic Viral Integration Site 1 Protein; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Thrombopoiesis - genetics
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2014.106567

MEIS1 is a transcription factor expressed in hematopoietic stem and progenitor cells and in mature megakaryocytes. This biphasic expression of MEIS1 suggests that the function of MEIS1 in stem cells is distinct from its function in lineage committed cells. Mouse models show that Meis1 is required for renewal of stem cells, but the function of MEIS1 in human hematopoietic progenitor cells has not been investigated. We show that two MEIS1 splice variants are expressed in hematopoietic progenitor cells. Constitutive expression of both variants directed human hematopoietic progenitors towards a megakaryocyte-erythrocyte progenitor fate. Ectopic expression of either MEIS1 splice variant in common myeloid progenitor cells, and even in granulocyte-monocyte progenitors, resulted in increased erythroid differentiation at the expense of granulocyte and macrophage differentiation. Conversely, silencing MEIS1 expression in progenitor cells induced a block in erythroid expansion and decreased megakaryocytic colony formation capacity. Gene expression profiling revealed that both MEIS1 splice variants induce a transcriptional program enriched for erythroid and megakaryocytic genes. Our results indicate that MEIS1 expression induces lineage commitment towards a megakaryocyte-erythroid progenitor cell fate in common myeloid progenitor cells through activation of genes that define a megakaryocyte-erythroid-specific gene expression program.