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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2578-2585.
Prepublished online as a Blood First Edition Paper on June 29, 2007; DOI 10.1182/blood-2007-02-073031.
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NEOPLASIA
Leukemia stem cells in a genetically defined murine model of blast-crisis CML
Sarah J. Neering1,
Timothy Bushnell1,2,
Selcuk Sozer3,
John Ashton4,
Randall M. Rossi1,
Pin-Yi Wang5,
Deborah R. Bell6,
David Heinrich7,
Andrea Bottaro1,7,8, and
Craig T. Jordan1,2,7
1 James P. Wilmot Cancer Center, and
2 Center for Pediatric Biomedical Research, University of Rochester Medical Center, NY;
3 Department of Microbiology and Immunology, University of Kentucky, Lexington;
4 Department of Biomedical Genetics, and
5 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, NY;
6 Markey Cancer Center, University of Kentucky, Lexington;
7 Department of Medicine, and
8 Department of Microbiology and Immunology, University of Rochester School of Medicine, NY
Myeloid leukemia arises from leukemia stem cells (LSCs), which are resistant to standard chemotherapy agents and likely to be a major cause of drug-resistant disease and relapse. To investigate the in vivo properties of LSCs, we developed a mouse model in which the biologic features of human LSCs are closely mimicked. Primitive normal hematopoietic cells were modified to express the BCR/ABL and Nup98/HoxA9 translocation products, and a distinct LSC population, with the aberrant immunophenotype of lineage–, Kit+/–, Flt3+, Sca+, CD34+, and CD150–, was identified. In vivo studies were then performed to assess the response of LSCs to therapeutic insult. Treatment of animals with the ABL kinase inhibitor imatinib mesylate induced specific modulation of blasts and progenitor cells but not stem- cell populations, thereby recapitulating events inferred to occur in human chronic myelogenous leukemia (CML) patients. In addition, challenge of leukemic mice with total body irradiation was selectively toxic to normal hematopoietic stem cells (HSCs), suggesting that LSCs are resistant to apoptosis and/or senescence in vivo. Taken together, the system provides a powerful means by which the in vivo behavior of LSCs versus HSCs can be characterized and candidate treatment regimens can be optimized for maximal specificity toward primitive leukemia cells.
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