ABSTRACT
I. INTRODUCTION A. Role and Significance of Genetic Abnormalities The Philadelphia (Ph) chromosome found in chronic myelogenous leukemia (CML) was the first chromosomal abnormality to be recognized as a specific, nonrandom re arrangement associated with cancer (1). Evidence that such chromosomal abnormalities play a direct role in the malignant process came from the molecular characterization of the t(8;14) translocation associated with Burkitt’s lymphomas (2). This translocation juxta poses the myc gene on chromosome 8q24 with immunoglobulin gene enhancer elements at 14q32 and results in deregulation of MYC expression (2). Myc, a member of the basic domain, helix-loop-helix (bHLH) family of transcription factors, binds DNA and activates transcription as a heterodimer with Max (for review see Ref. 4). Myc/Max heterodimerization was shown to be required for transformation by Myc (for review see [3]). Mice over expressing the MYC gene under control of the C|i enhancer develop B-cell lymphoma, indicating that in Burkitt s lymphomas the initiating event in the process that will lead to malignant transformation is transcriptional activation of the MYC oncogene (for review see Refs. 3 and 4). Since the time of these initial studies, many other chromosomal re arrangements have been characterized, and the genes involved have been cloned and in some instances their function has been extensively studied. Indeed, oncogene deregulation through juxtaposition to enhancer elements of the immunoglobulins or T-cell receptor (TCR) genes is now known to be a major mechanism of oncogene activation and to be an initiating event in many leukemias and lymphomas (3). Translocations involving the immunoglobulins or TCR loci are thought to occur during the physiological rearrangement
steps that give rise to functional antigen receptor genes (5). The clone carrying the translo cation, can, in most instances, differentiate further and will accumulate additional genetic changes giving rise to the phenotype and morphology of the neoplasm (6).
