STABILITY OF AML1 (CORE) SITE ENHANCER MUTATIONS IN T-LYMPHOMAS INDUCED BY ATTENUATED SL3-3 MURINE LEUKEMIA-VIRUS MUTANTS

Murine retrovirus SL3-3 is highly T lymphomagenic. Its pathogenic prop erties are determined by the transcriptional enhancer of the U3 repeat region which shows preferential activity in T cells, Within the U3 re peats, the major determinant of T-cell specificity has been mapped to binding sites for the AML1 transcription factor family (also known as the core binding factor [CBF], polyomavirus enhancer binding protein 2 [PEBP2], and SL3-3 enhancer factor 1 [SEF-1]). SL3-3 viruses with AML 1 site mutations have lost a major determinant of T-cell-specific enha ncer function but have been found to retain a lymphomagenic potential, although disease induction is slower than for the SL3-3 wild type. To compare the specificities and mechanisms of disease induction of wild -type and mutant viruses, we have examined lymphomas induced by mutant viruses harboring transversions of three consecutive base pairs criti cal to AML1 site function (B. Hallberg, J. Schmidt, A. Luz, F. S. Pede rsen, and T. Grundstrom. J. Virol. 65:4177-4181, 1991). Our results sh ow that the mutated AML1 sites are genetically stable during lymphomag enesis and that ecotropic provirus numbers in DNA. of tumors induced b y wild-type and mutant viruses fall within the same range, Moreover, p roviruses were found to be integrated at the e-myc locus in similar pr oportions of wild-type and mutant SL3-3-indured tumors, and the mutate d AML1 sites of proviruses at c-myc are unaltered, In some cases, howe ver, including one c-myc-integrated provirus, a single-base pair chang e mas detected in a second, weaker AML1 binding site, By DNA rearrange ment analysis of the T-cell receptor p-locus, tumors induced by the AM L1 site mutants are found to be of the T-cell type, Thus, although the AML1 site mutants have weakened T-cell-specific enhancers they are T- lymphomagenic, and wild-type- and mutant-virus-induccd tumor DNAs are similar with respect to the number of overall ecotropic and c-myc-inte grated clonal proviruses. The SL3-3 wild-type and AML1 site mutant vir uses may therefore induce disease by similar mechanisms.