Oncogene Activation by Chromosomal Translocations in B Cell-Derived Tumors

Abstract

This chapter reviews the current evidence concerning the mechanisms of oncogene activation by chromosomal translocations and its role in Burkitt lymphoma (BL), mouse plasmacytoma (MPC), and rat immunocytoma (RIC). The following aspects are discussed. (1) Does the cis relationship between the c-myc oncogene and one of the three Ig loci play a causative role in the genesis of these tumors? (2) How does the juxtaposition activate the myc gene? (3) What is the functional role of the translocation in the tumorigenic process? Only the first question can be answered with some certainty. In BL, the translocation has been found in 100% of the properly investigated cases so far, with no difference between endemic or nonendemic, EBV-carrying or EBV-negative cases. One exceptional line, BJAB, can be disregarded, since it is not a typical BL. In RIC, all tumors so far studied had the translocation. In MPC, only about 90% of the MPCs carry the translocations. High resolution banding of some translocation-negative MPCs has shown that they carry an interstitial deletion in the D2/D3 region of chromosome 15, corresponding to the location of the myc gene. Molecular analysis showed a complex rearrangement that has led to the juxtaposition of c-myc and IgH suites sequences, and must have arisen by at least two independent translocations and one inversion. A similarly complex rearrangement was found in the first RIC that has been examined. The regularity of the association between the translocation events and the tumors in which they occur, together with the full analogy between the human, mouse, and rat systems can be interpreted only by postulating that the activation of c-myc by the translocation represents an essential step in the genesis of these tumors. The transposed myc gene becomes constitutively activated. In all probability, this renders the gene resistant to cell cycle and differentiation-dependent regulations that govern its expression in the normal chromosomal location. The way in which myc activation contributes to the escape of the EBV-carrying or EBV-negative BL cell from immune and nonimmune controls is considered. The hypothesis is advanced that the translocation affects B cells at the point at which an antigen-activated cell is about to leave the proliferative process, upon the waning of the antigenic stimulus, and enters a program that would normally lead it toward a long-lived memory cell.