HMGA2 Promotes Long-Term Engraftment and Myelo-Erythroid Differentiation of Human Hematopoietic Stem and Progenitor Cells

Identification of determinants of fate choices in hematopoietic stem cells (HSCs) is essential in order to improve the clinical use of HSCs and to enhance our understanding of the biology of normal and malignant hematopoiesis. Here we show that high mobility group AT hook 2 (HMGA2), a non-histone chromosomal binding protein, is highly and preferentially expressed in HSCs and the most immature progenitor cell subsets of fetal, neonatal and adult human hematopoiesis. Knockdown of HMGA2 by shRNA impaired the long-term hematopoietic reconstitution of cord blood (CB) derived CB CD34+ cells. Conversely, overexpression of HMGA2 in CB CD34+ cells led to an overall enhanced reconstitution in serial xenotransplantation assays accompanied by a skewing towards the myeloerythroid lineages. RNA-Seq analysis showed that enforced HMGA2 expression in CD34+ cells induced gene expression signatures associated with differentiation towards megakaryocyte-erythroid and myeloid lineages, as well as signatures associated with growth and survival, which at the protein level were coupled with a strong activation of AKT. Taken together our findings demonstrate a key role of HMGA2 in regulation of both proliferation and differentiation of human HSPCs. Overall design: RNA-Seq on control and HMGA2 transduced CD34+ cells.