The Inversion 16 (inv16) and t(8;21) chromosomal abnormalities are associated with a specific disease morphology and a relatively good prognosis in acute myelogenous leukemia. The genes encoded about each breakpoint have been cloned by the investigators as have the fusion cDNAs encoded by the chimeric genes. Core binding factor (CBF - formerly known as PEPB2), is a heterodimeric transcription factor formed by the alpha and beta subunit CBF gene products. The inv(16) causes a fusion of 5' coding sequences of CBFB (encoded at 16q22) to the MYH11 (a myosin heavy chain gene) 3' coding sequences (16p13). t(8;21) fuses AML1, encoding the alpha factor gene of the same transcription factor CBF (at 21q22 ), to another gene ETO (8q22). It is hypothesized that CBFB-MYH11 or AML1-ETO chimeric gene products may cause leukemia when expressed in hematopoietic progenitors. It is further hypothesized that the CBF transcription factor is of considerable importance in the regulation of hematopoiesis and may be involved in the pathogenesis of other leukemias. This project will aim to: l)Assess the effects on cell lines of expression of CBFB-MYH11 and AML1-ETO fusion proteins. Phenotypic changes including loss of differentiation, reversal of growth factor dependance, alterations in cell cycle and Cytosine Arabinoside sensitivity will be studied. 2) Test the effects of in vivo CBFB-MYH11 expression in mice or after retroviral transduction for expression in mouse bone marrow or via expression in transgenic animals. 3) Examine CBFB- MYH11 expression at various levels of hematopoietic differentiation and at various disease stages in patient samples. These experiments will define important biological and chemical properties of this novel chimeric gene and yield insights into the physiology of the normal CBF and its role in differentiation.
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