The Philadelphia (Ph) chromosome is a specific chromosomal abnormality found in chronic myelocytic leukemia (CML) and in a percentage of cases of acute lymphocytic leukemia (ALL). This chromosome is a result of a reciprocal translocation between chromosomes 22 and 9; on a molecular level, two genes, the BCR gene on chromosome 22 and the ABL oncogene from chromosome 9, become fused to form a chimeric gene. The chimeric gene produces an abnormal protein which exhibits altered enzymatic activity. All data indicate that this abnormal protein is involved in the causation and/or maintenance of CML and Ph-positive ALL; however, to date, there is only limited evidence for this and the normal cellular functions of the ABL and BCR gene products remain unknown. The long term objective of this proposal is to directly examine the function of the abnormal BCR/ABL and normal BCR and ABL genes in vivo, To this end, BCR/ABL constructs will be introduced into the mouse germline and transgenic BCR/ABL mice will be examined for the development of leukemia and/or other malignancies. In addition, mice overexpressing the normal BCR and ABL genes will be generated. However, success of the experiments described above is, to a certain extent, dependent upon the question whether or not ABL and/or BCR gene expression will interfere with embryonic development of the mouse. To circumvent this potential problem, the constructs will therefore also be introduced into embryonic stem cells and reintroduced in vivo through blastocyst injection and reimplantation; in this way, potential detrimental effects can be limited to a small percentage of somatic cells. It is intended to develop both P210 and P190 expressing mice; if the transgenic mice develop leukemia, lines will be established and the preleukemic phase, expression, cell type affected, kinetics of the disease and karyotypic abnormalities will be studied. In addition, the type(s) of disease generated by the different constructs will be compared.
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