Introduction of a cis-acting mutation in the capsid-coding gene of moloneymurine leukemia virus extends its leukemogenic properties

Inoculation of newborn mice with the retrovirus Moloney murine leukemia vir us (MuLV) results in the exclusive development of T Lymphomas with gross th ymic enlargement. The T-cell leukemogenic property of Moloney MuLV has been mapped to the U3 enhancer region of the viral promoter. However, we now de scribe a mutant Moloney MuLV which can induce the rapid development of a un iquely broad panel of leukemic cell types. This mutant Moloney MuLV with sy nonymous differences (MSD1) was obtained by introduction of nucleotide subs titutions at positions 1598, 1599, and 1601 in the capsid gene which mainta ined the wild-type (WT) coding potential. Leukemias were observed in all MS D1-inoculated animals after a latency period that was shorter than or simil ar to that of WT Moloney MuLV. Importantly, though, only 56% of MSD1-induce d leukemias demonstrated the characteristic thymoma phenotype observed in a ll WT Moloney MuLV leukemias. The remainder of MSD1-inoculated animals pres ented either with bona fide clonal erythroid or myelomonocytic leukemias or , alternatively, with other severe erythroid and unidentified disorders. Am plification and sequencing of U3 and capsid-coding regions showed that the inoculated parental MSD1 sequences were conserved in the leukemic spleens, This is the first report of a replication-competent MuLV lacking oncogenes which can rapidly lead to the development of such a broad range of leukemic cell types. Moreover, the ability of MSD1 to transform erythroid and myelo monocytic lineages is not due to changes in the U3 viral enhancer region bu t Father is the result of a cis-acting effect of the capsid coding gag sequ ence.