Lessons from Translocations and Transgenic Mice: Constitutive c-myc Expression Predisposes to Neoplasia

The predominant chromosome translocations associated with Burkitt lymphomas of man and plasmacytomas of the mouse result from recombination of the c- myc protooncogene with the immunoglobulin heavy chain locus. The crucial outcome of this event is deregulation of c- myc expression. The hypothesis that constitutive myc expression highly predisposes to tumorigenesis has now been amply vindicated by studies with transgenic mice. Animals bearing a c- myc gene coupled to the immunoglobulin μ or κ enhancer frequently develop a fatal lymphoma, Eμ being particularly effective. The lymphoid regulatory elements play an essential role because transgenic mice carrying either a “normal” c- myc gene or a gene lacking the putative 5′ regulatory region fail to develop tumors. The tumors in Eμ- myc mice are all B lymphoid in origin and monoclonal. Tumorigenesis is preceded by a benign polyclonal proliferation of early B lineage cells which is evident as early as 18 days of gestation. Characterization of this preneoplastic phase induced by the deregulated c- myc gene suggests that the level of c- myc expression is a crucial factor in determining the balance between self-renewal and maturation within a differentiation lineage.