SUPPRESSIBLE AND NONSUPPRESSIBLE AUTOCRINE MAST-CELL TUMORS ARE DISTINGUISHED BY INSERTION OF AN ENDOGENOUS RETROVIRAL ELEMENT (IAP) INTO THE INTERLEUKIN-3 GENE

After v-H-ras expression, the interleukin 3 (IL-3)-dependent PB-3c mast cells progress in vivo to two different classes of IL-3 autocrine tumors. Class I tumors show a germline configuration of the IL-3 gene and represent more than 90% of tumors analyzed so far. Somatic cell fusion of class I tumor lines with the nontumorigenic parental PB-3c resulted in loss of oncogenic IL-3 expression by a posttranscriptional mechanism with concomitant tumor suppression. Class II tumors arise rarely and contain an insertion in one IL-3 allele. This alteration was linked to enhanced IL-3 gene transcription. For one tumor, the insertion was shown to be an endogenous retroviral element (intracisternal A-particle). Cell hybrids of class II tumors with PB-3c remained IL-3 independent, expressed IL-3, and formed tumors rapidly. These results suggest that the v-H-ras oncogene synergizes with a recessive and a dominant lesion in class I and II tumors, respectively, both of which lead to the autocrine production of IL-3.