Constitutive Expression of the ABC Transporter ABCG2 Enhances the Growth Potential of Early Human Hematopoietic Progenitors

¹ Department of Medicine III, University of Munich- Grosshadern, Munich, Germany, Clinical Cooperative Group Leukemia, GSF-National Research Center for Environment and Health, Munich, Germany
² Department of Translational Oncology, The National Center for Tumor Diseases (NCT) and the German Cancer Research Center, Heidelberg, Germany

^* To whom correspondence should be addressed. E-mail: feuring{at}gsf.de.

	Abstract

The ATP binding cassette transporter, ABCG2, is a molecular determinant of the side population phenotype, which is enriched for stem and progenitor cells in various non-hematopoietic and hematopoietic tissues. ABCG2 is highly expressed in hematopoietic progenitors and silenced in differentiated hematopoietic cells, suggesting a role of ABCG2 in early hematopoiesis. To test whether ABCG2 is involved in human hematopoietic development, we retrovirally transduced umbilical cord blood derived early hematopoietic cells and analyzed hematopoiesis in vitro and in vivo. ABCG2 increased the number of clonogenic progenitors in vitro, including the most primitive clonogenic cells forming CFU-GEMM by 2fold (n=14, p<0.0005). Furthermore, ABCG2 induced a 3 fold increase in the re-plating capacity of primary colonies (n=9, p<0.01). Additionally, ABCG2 impaired the development of CD19⁺ lymphoid cells in vitro. In transplanted NOD/SCID mice, the ABC transporter decreased the number of human B-lymphoid cells, resulting in an inversion of the lymphoid/myeloid ratio. ABCG2 enhanced the proportion of CD34⁺ progenitor cells in vivo (n=4, p<0.05), and enhanced the most primitive human progenitor pool as determined by limiting dilution CRU assay (p<0.034). Our data characterize ABCG2 as a regulatory protein of early human hematopoietic development.