Cas NS-1 is an acutely transforming murine retrovirus that induces pre-B and pro-B cell lymphomas. Molecular cloning showed it was generated from the ecotropic Cas-Br-M virus by sequential recombinations with endogenous retroviral sequences and a cellular oncogene. The oncogene sequence shows no homology with known oncogenes but some similarity to the yeast transcriptional activator GCN4. A 100-kDa gag-cbl fusion protein, with no detectable kinase activity, is responsible for the cellular transformation. The cellular homologue of v-cbl, present in mouse and human DNA, is expressed in a range of hemopoietic lineages.The ability of retroviruses to recombine with host chromosomal DNA has enabled the identification of genes with cancer-causing potential, collectively known as oncogenes (for reviews, see refs. 1-3). From studies of avian and mammalian retroviruses numerous oncogenes have been isolated and this has led to dramatic progress in the definition and understanding of the molecular basis of cancer. We have been examining the tumors that develop in mice after infection with an ecotropic retrovirus called Cas-Br-M. This virus was originally isolated from a wild mouse of the Lake Casitas region of California (4) and induces T-and B-cell lymphomas, erythroleukemia, and myeloid leukemia with latent periods of 5-8 months (5). It remains unclear whether Cas-Br-M generates this range of tumors by infecting multipotential hemopoietic cells or by infecting cells committed to a lineage. Furthermore, the etiological agent in some of these tumors is a recombinant virus formed soon after inoculation (6). This class of murine retrovirus is termed mink cell focus-forming (MCF) virus and evolves by recombination between the infecting ecotropic virus and nonecotropic retroviral sequences present in the mouse genome (7,8).To determine the relative importance of Cas-Br-M and MCF viruses in the induction of hemopoietic neoplasms, cell-free extracts were prepared from a range of tumors arising in NFS/N mice inoculated at birth with Cas-Br-M (6). These extracts were inoculated into newborn NFS/N mice since it was reasoned if Cas-Br-M was the tumor-inducing virus, then each extract should produce a range of tumor phenotypes with a long latent period. Alternatively, if lineage-specific MCF viruses in the extracts were the dominant tumor-inducing agents, then the tumors should correspond to the primary tumor and the latency should be reduced. The results from 3 of 12 extracts tested were consistent with the latter possibility (6).One of the three extracts producing a high proportion of tumors with the same phenotype as the primary tumor and a reduced latency was called Cas NS-1. This extract was prepared from the spleen of a mouse with a pre-B cell lymphoma that developed 28 weeks after Cas-Br-M infection. Injection of the Cas NS-1 extract into newborn NFS/N mice resulted in a high proportion of pre-B cell lymphomas with a mean latent period of 16 weeks. This result indicated that a tumorigenic virus with a lineage preference...

Hemopoietic lineage switching occurs when leukemic cells, apparently committed to one lineage, change and display the phenotype of another pathway. cDNA representational difference analysis was used to identify myeloid-specific genes that may be associated with an erythroid to myeloid lineage switch involving the murine J2E erythroleukemic cell line. One of the genes isolated (HLS7) is homologous to the novel human oncogene myeloid leukemia factor 1 (MLF1) involved in the t(3;5)(q25.1;q34) translocation associated with acute myeloid leukemia. Enforced expression of HLS7 in J2E cells induced a monoblastoid phenotype, thereby recapitulating the spontaneous erythroid to myeloid lineage switch. HLS7 also inhibited erythropoietin-or chemically-induced differentiation of erythroleukemic cell lines and suppressed development of erythropoietin-responsive colonies in semi-solid culture. However, intracellular signaling activated by erythropoietin was not impeded by ectopic expression of HLS7. In contrast, HLS7 promoted maturation of M1 monoblastoid cells and increased myeloid colony formation in vitro. These data show that HLS7 can influence erythroid/myeloid lineage switching and the development of normal hemopoietic cells.

No abstract