AKXD-23 recombinant inbred mice develop myeloid tumors at a high frequency, unlike other AKXD recombinant inbred strains which develop B-cell lymphomas, T-cell lymphomas, or both. AKXD-23 myeloid tumors are monoclonal, and their DNA contains somatically acquired proviruses, suggesting that they are retrovirally induced. We identified a common site of ecotropic proviral integration that is present in the DNA of all AKXD-23 myeloid tumors that were analyzed and in the DNA of all myeloid tumors that occur in AKXD strains othefr than AKXD-23. We designated this locus Evi-l (ecotropic viral integration site 1). Rearrangements in the Evi-l locus were also detected in the DNA of a number of myeloid tumors and myeloid cell lines isolated from strains other than AKXD. In contrast, few Evi-l rearrangements were detected in the DNA of Tor B-cell tumors. Evi-) may thus identify a new proto-oncogene locus that is involved in myeloid disease.Mice from 21 of 23 AKXD recombinant inbred mouse strains derived from AKR/J, a strain with a high incidence of lymphoma, and DBA/2J, a strain with a low incidence of lymphoma, develop hematopoietic neoplasms at a high frequency (27; D. J. Gilbert, unpublished data). However, the average age of onset and the cell type of hematopoietic neoplasms varies from strain to strain, suggesting that in these strains a number of genes that affect susceptibility to lymphoma and disease type have been segregated during inbreeding. Mice from six of the AKXD strains died predominantly of T-cell lymphomas, mice from six strains died predominantly of B-cell lymphomas, and mice from one strain died predominantly of myeloid tumors. Mice from eight strains were equally susceptible to lymphomas of T-or B-cell origin.Most AKXD lymphomas are monoclonal, as evidenced by clonal integrations of somatically acquired proviruses into their DNA (26; D. J. Gilbert, unpublished data). This finding is consistent with the hypothesis that viral integration is causally associated with lymphoma induction. Newly acquired clonal proviral integrations have also been observed by many laboratories in which lymphomas that arise in other highly viremic, highly lymphomatous mouse strains are studied (1, 2,43,44). While somatic integrations of mink cell focus-forming (MCF) proviruses have most often been associated with T-cell lymphomas (4,5,9,23,33), somatic ecotropic proviruses are usually associated with B-cell and myeloid tumors (1, 2, 44). A similar situation exists in AKXD strains (26; D. J. Gilbert, unpublished data).DNAs from 258 AKXD hematopoietic neoplasms were recently characterized to determine whether they contain virally induced rearrangements in seven known or putative proto-oncogene loci found previously to serve as common ). These loci included Myc, Myb, Fis-1, Pim-1, Pvt-J, Mlvi-1, and Mlvi-2. With the exception of Myb, virally induced rearrangements were identified in all loci. Most of these rearrangements were detected in the DNA of T-cell lymphomas; few rearrangements were detected in the DNA of B-cell lymphomas o...