Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo.
Hematopoietic stem cells (HSCs) can be identified by a "side population" (SP) phenotype. Previous studies have implicated the ATP binding cassette transporter genes Mdr1a/1b and/or Bcrp1 in the SP phenotype. To define the relative role of these transporters, we generated Bcrp1 null mice and evaluated HSCs both functionally and phenotypically. Loss of Bcrp1 gene expression, but not Mdr1a/1b, led to a significant reduction in the number of SP cells in the bone marrow and in skeletal muscle. In the bone marrow, there was a nearly absolute loss of lineage negative, c-Kit-positive, Sca-1-positive SP cells, and the residual SP cells were depleted of repopulating cells in a transplant assay, demonstrating that Bcrp1 expression is necessary for the SP phenotype in HSCs. Furthermore, Bcrp1 null hematopoietic cells were significantly more sensitive to mitoxantrone in drug-treated transplanted mice. These results show that Bcrp1 gene expression alone defines the SP stem cell phenotype, and suggest that the physiological function of Bcrp1 expression in HSCs is to provide protection from cytotoxic substrates.
Zhou
Sheng
S
Division of Experimental Hematology, Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. sheng.zhou@stjude.org
Morris
John J
JJ
Barnes
Yuxiao
Y
Lan
Lubin
L
Schuetz
John D
JD
Sorrentino
Brian P
BP
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002452:Cell Count; D005260:Female; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008942:Mitoxantrone / Q000633:toxicity; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009363:Neoplasm Proteins; D010641:Phenotype; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D008942:Mitoxantrone; D009363:Neoplasm Proteins; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C116614:ABCG2 protein, human; C095122:multidrug resistance protein 3