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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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Submitted February 7, 2007
Accepted June 22, 2007
Leukemia stem cells in a genetically defined murine model of blast crisis CML
Sarah J Neering, Timothy Bushnell, Selcuk Sozer, John Ashton, Randall M Rossi, Pin-Yi Wang, Deborah R Bell, David Heinrich, Andrea Bottaro, and Craig T Jordan*
James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, United States
Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, NY, United States
Department of Microbiology and Immunology, University of Kentucky, Lexington, KY, United States
Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, NY, United States
Department of Pathology and Laboratory Medicine, University of Rochester School Medical Center, Rochester, NY, United States
Markey Cancer Center, University of Kentucky, Lexington, KY, United States
Department of Medicine, University of Rochester School of Medicine, Rochester, NY, United States
Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY, United States
* Corresponding author; email: craig_jordan{at}urmc.rochester.edu.
Myeloid leukemia arises from leukemia stem cells (LSC), 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 LSC, we developed a mouse model in which the biological features of human LSC 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 LSC 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 CML patients. In addition, challenge of leukemic mice with total body irradiation was selectively toxic to normal HSC, suggesting that LSC are resistant to apoptosis and/or senescence in vivo. Taken together, the system provides a powerful means by which the in vivo behavior of LSC vs. HSC can be characterized and candidate treatment regimens can be optimized for maximal specificity towards primitive leukemia cells.
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