Many retroviruses that carry oncogenes (acute transforming viruses) are generally replication-defective and therefore require co-infection with a replication competent 'helper' retrovirus for infectivity. The helper virus provides the retroviral proteins necessary for particle production and infection. These include the envelope glycoproteins that specifically bind to cell surface receptors and mediate viral adsorption and entry. Thus, a particular helper virus may influence the nature of disease induced by an oncogene-containing retrovirus due to tissue tropism of the helper. In a previous study, a replication-defective recombinant Moloney murine leukemia virus containing the v-myc oncogene was generated (M-MuLV(myc); Brightman B.K., Pattengale P.K., and Fan H., J Virol 60: 68-81, 1986). When M-MuLV(myc) was inoculated into mice using the non-pathogenic amphotropic murine leukemia virus (Am-MuLV 4070) as a helper, T- and B-lymphoblastic lymphomas resulted with the following two surface phenotypes, namely, (1) Thy 1.2+, B220- and (2) Thy 1.2-, B220+. Thy 1.2 surface antigen is characteristic of cells of the lymphoid lineage, whereas B220 surface antigen is characteristic of cells of the B-lymphoid lineage. In these experiments, to assess the influence of the helper virus on the disease specificity of M-MuLV(myc), two weakly pathogenic ecotropic helper MuLVs that interact with different cell surface receptors than Am-MuLV (Mo+PyF101 and AKV MuLV) were used to pseudotype M-MuLV(myc). In both cases, when inoculated into mice, these pseudotypes induced only T-lymphoblastic lymphoma. These results indicate that for M-MuLV(myc) the types of the tumors induced are influenced by the helper virus utilized, and they suggest that different lymphoid cells may express different levels of retroviral receptors.