UC Irvine

Models of chronic myeloid leukemia (CML) have proven invaluable for furthering our understanding of the molecular pathophysiology of this disease. Xenotransplantation of primary human CML cells into immunodeficient mice allows investigation into the nature of the most primitive repopulating cells in this leukemia, but the system is limited by variability and difficulty with experimental manipulation. Accordingly, a large effort has been invested in developing models of CML through expression of the BCR/ABL oncogene in the hematopoietic system of laboratory mice. Despite numerous attempts, an accurate transgenic mouse model of CML has not been produced, possibly because of the toxicity of BCR/ABL. Conditional transgenic mice are a promising new approach to this problem. A more successful strategy is retroviral transduction of BCR/ABL into mouse bone marrow in vitro, followed by transplantation into syngeneic or immunodeficient recipient mice. Recipients of marrow transduced with p210 BCR/ABL develop a fatal myeloproliferative illness that closely resembles human CML. This model is being used to define the signaling pathways required for leukemogenesis by BCR/ABL, and for developing new therapeutic approaches.