Hematopoietic cells from mice that are deficient in both Bcrp1/Abcg2 and Mdr1a/1b develop normally but are sensitized to mitoxantrone

摘要

Mdrla/1b and Bcrpl/Abcg2 are two members of the ATP binding cassette transporter superfcitnily. They are highly expressed In hemaiopoietie stem cells (HSCs) and down-regulated upon hematopoietie maturation. The expression of Mdr1a/1b (tightly linked genes in a single locus) confers low rhodamine I23 fluorescence, and the expression of Bcrpl confers low Hoechst 33342 fluorescence, which results in the side pormlation (SP) phenotype in HSCs. Studies using Mdrla/lb or Bcrpl knock-out mice have shown that these two transporters protect HSCs against the toxicity of chemotherapeuric drugs such as mifoxantrone and possibly other naturally occurring xenohiotic substrates, but their relative role is undefined. A potentially important role of Mdrla/lb and/orBcrpl in the development of hematopoietic cells has been implicated by their conserved expression in HSCs and by overexpression studies. Overexpression of MORI in HSCs by retrovirus transducnon led to HSC expansion, myeloproliteration, and leukemia. while overexpression of BCRP in HSCs disrupted their normal differentiation. However, no abnormality in hematopoietic development has been observed in mice lacking either Mdrl a/ 1b or Bcrpl. Because Mdrla/lb and Bcrpl share many substrates such as mitoxantrone, Hoechst 33342. and eloposide. it is unknown whether Mdrto/lb and Bcrpl perform redundant functions in hematopoietic development and in the protection of hematopoietic cells against xenobiotic substrates. To answer these questions, we generated micelacking both Mdrla/lb and Bcrpl expression and examined their hematopoietic system specifically, as well as the sensitivity of hematopoietic cells from these mice to mitoxuntrone, a known cytotoxic substrate for both transporters.