Constitutive activation of oncogenes by chromosomal translocations in B-cell derived tumors.

Abstract

The mechanisms of chromosomal translocations and its role in Burkitt lymphoma (BL), mouse plasmacytoma (MPC) and rat immunocytoma (RIC) are discussed with particular emphasis on the following questions: 1) Does the cis-relationship between the c-myc oncogene and one of the 3 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? Question 1) can be answered with some certainty. In BL, the translocation has been found in 100% of 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 examined tumor had the translocations so far. Only 90% of the MPCs carry the translocations, but high resolution banding of some translocation negative MPCs has shown that they carry an interstitial deletion in the D2/D3 region of Chr. 15, corresponding to the myc locus. Molecular analysis showed a complex rearrangement that has led to the juxtaposition of c-myc and IgH-switch sequences. Sequencing data indicated that they 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 where they occur, together with the similarities between the human, mouse and rat systems can be interpreted by postulating that the activation of c-myc by the translocation represents an essential step in the genesis of these tumors. 2) 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. 3) The hypothesis is advanced that the translocation affects B-cells at the point where an antigen activated cell is about to leave the proliferative process, upon the waning of the antigenic stimulus, and enters a program towards a long lived memory cell.