chapter  6
32 Pages

Animal models of Philadelphia-positive leukemia Richard A Van Etten

WHY USE ANIMAL MODELS OF Ph-POSITIVE LEUKEMIA?

The BCR/ABL oncogene was first isolated in 19841 and found to be a fusion of BCR and cABL. Shortly thereafter, the product of this chimeric gene, BCR/ABL, was shown to be a dysregulated tyrosine kinase2 capable of transformation of primary bone-marrow-derived Blymphoid cells in vitro.3 Subsequent studies demonstrated that BCR/ABL could weakly transform Rat-14 and NIH 3T35 fibroblasts to anchorage independence. Finally, BCR/ABL was shown to transform cytokine-dependent lymphoid6 and myeloid7 hematopoietic cell lines to become independent of cytokine for survival and proliferation. These semiquantitative assays demonstrated that BCR/ABL is a classical oncogene, allowed a comparison of the transforming activity of different isoforms of BCR/ABL,8,9 and permitted mutagenic analysis of the requirements for different structural domains of BCR/ABL for transformation.10,11

Studies in cell lines and primary cells in vitro demonstrated that BCR/ABL constitutively activated many cell signaling pathways,12 sev-

eral of which were demonstrated to be required for transformation. Given the ready availability of these different in vitro assays for BCR/ABL function and the wealth of information gleaned from them, the question might naturally arise why animal models of BCR/ABL-induced leukemia are needed?