AN SL3-3 MURINE LEUKEMIA-VIRUS ENHANCER VARIANT MORE PATHOGENIC THAN THE WILD-TYPE OBTAINED BY ASSISTED MOLECULAR EVOLUTION IN-VIVO

SL3-3 is a highly T-lymphomagenic murine retrovirus in which the trans criptional enhancer is a major oncogenic determinant. Here, we describ e an SL3-3 enhancer variant that induced T-cell lymphomas in all inocu lated mice with a shorter latency period than wild-type SL3-3. The enh ancer repeat region of this variant contains two deletions encompassin g the nuclear factor 1 binding sites in addition to an additional inta ct enhancer repeat element. Tumors induced by this variant were T-cell lymphomas, as indicated by T-cell receptor rearrangements, and contai ned the input provirus enhancer regions. The variant was the result of mutation of specific transcription factor binding sites in the viral enhancer, isolation of rare second-site enhancer variants from the res ulting induced tumors, and subsequent restoration of the original firs t-site mutations of one such variant. We have termed this process assi sted molecular evolution.