THE Et.-myc TRANSGENIC MOUSE A Model for High-incidence Spontaneous Lymphoma and Leukemia of Early B Cells

Translocation of the c-myc protooncogene into or near one of the Ig loci is found in almost every case of Burkitt's B cell lymphoma in man and experimentally induced plasma cell tumor in the mouse (reviewed in references 1, 2) . This accidental rearrangement of the cellular genome appears to free the c-myc gene from its normal susceptibility to negative regulation and to render it constitutively active in cells that express Ig genes (reviewed in references 1-4) . The contribution of the rearranged gene to the neoplastic phenotype may stem from the ability ofthe myc polypeptide to drive cellular proliferation, perhaps by promoting DNA replication (5, 6) . While its biochemical function is not yet defined, c-myc expression normally correlates closely with cell-cycle activity in a broad range of cell types, increasing greatly when resting cells are mitogenically stimulated and declining when they cease to proliferate (3, 4, 7) . The effects of altered oncogenes on cells in their natural environment can be assessed through the use of transgenic mice (8, 9) . A transgenic strain is initiated by inserting a gene into the mouse genome and is perpetuated thereafter by normal breeding . By this means, a c-myc gene coupled to regulatory sequences from the mousemammary tumor virus was shown to cause mammary carcinomas, and sometimes other tumors, after a substantial latent period (10, 11). To mimic the translocated myc genes found in lymphoid tumors, we introduced into mice a DNA sequence, designated EA-myc, isolated from a mouse plasmacytoma in which a normal myc gene had become coupled to the Ig heavy chain enhancer (12) . In the resultant transgenic mice, the El-myc transgene appears to be expressed exclusively in B-lymphoid cells (13) and causes them to proliferate more than normal (14) . Starting before birth, the pre-B cell population expands progressively up to about five times its normal size, while B cells are somewhat reduced in number despite their increased cell-cycle activity (14) . The immune