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Symposium 31: ABC Transporters and Cancer Biology and Treatment

The role of Abcg2 expression in hematopoietic stem cells

St. Jude Children’s Research Hospital, Memphis, TN

Abstract

SY31-2

The Side Population (SP) assay is used for the enrichment of hematopoietic stem cells (HSCs), however this assay is not specific for HSCs and causes toxicity when cells are exposed to Hoechst dye. The SP phenotype has been associated with expression of the Abcg2 transporter, which is expressed in HSCs and mediates Hoechst dye efflux. To explore the functional effects of Abcg2 expression in HSCs, we have generated Abcg2 knockout mice and shown that Abcg2 null HSCs are dramatically sensitized to mitoxantrone, suggesting that the function of Abcg2 in HSCs is to protect from naturally occurring toxic substrates and mutagens. These data have relevance to AML, where malignant HSCs may co-opt resistance mechanisms present in normal HSCs. In our most recent work, we have asked whether expression of Abcg2 would allow for prospective isolation of HSCs. Mice were generated with a GFP reporter gene inserted into the Abcg2 locus. Bone marrow cells that expressed GFP and lacked expression of lineage-specific markers (Lin^-) were isolated by flow cytometry and tested for HSC activity. Irradiated recipient mice were reconstituted with as little as 10 cells, while as many as 60,000 Lin^-, GFP^- cells gave no reconstitution. Secondary transplant studies confirmed that the Lin^-, GFP⁺ cells were indeed long term repopulating, self-renewing HSCs. These results show that essentially all murine HSCs express Abcg2, and that Abcg2 expression provides a new and simple purification strategy for HSCs. Furthermore, we have identified populations of Abcg2-expressing cells in the skeletal muscle that may represent non-hematopoietic stem cells.