Abstract
The purpose of this study was to characterize the phenotype and analyze the functional characteristics of CML stem cells (CML-SCs) in a mouse model system. A retrovirus transduction model was employed using a vector expressing p210/BCR/ABL and the green fluorescent protein (GFP). Transplantation studies of BCR/ABL infected cells in recipient mice demonstrated an aggressive myeloproliferative disease within approximately 3 weeks, as has previously been observed with this approach. Phenotypic analysis of bone marrow from BCR/ABL mice showed contribution by the transduced cells to multiple lineages, suggesting a primitive stem/progenitor cell gives rise to the disease. Subsequent analysis of primary cells that arise in vivo showed the leukemia-initiating activity resides in cells that are Sca-1+/c-kit+/Lin-. Cell cycle analyses (as detected by BrdU incorporation) of the Lin−/c-kit+/Sca-1+ compartment of BCR/ABL mice demonstrated an enhanced cycle rate (approximately 2-fold) in the leukemic population, signifying a possible increase in the self-renewal or proliferative properties of this primitive compartment that could lead to development/progression of the disease. Further, comparison of the BCR/ABL mice and GFP control mice revealed preferential over-expression of CD24 (heat-stable antigen) in the primitive leukemic cells (90% vs. 52% in normal counterparts) demonstrating a possible BCR/ABL induced activation of the antigen. Sorting and serial transplantation studies of CD24+ vs CD24− cells from BCR/ABL mice showed that the leukemia-initiating activity resides in the CD24+/Lin− population. Collectively, these data indicate that BCR/ABL expression increases proliferation of primitive CML cells and up-regulates the CD24 antigen. We suggest that the CD24 antigen represents a potential marker to distinguish normal from CML stem cells and that it may confer specific functional properties on the CML population.
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