We have been studying molecular mechanisms governing lymphoid cell differentiation and neoplasia. We have discovered a role for dlk in cell-cell interactions between stromal cells and precursor B cells. Stromal cells arise from mesenchymal stem cells (MSC) while pre-B cells arise from hematopoietic stem cells (HSC), both of which can be found in the bone marrow microenvironment. Dlk is a member of the EGF-like homeotic gene family which influences cell fate during development. Our work has shown that dlk mediates cell-cell contact between stromal cells and precursor B cells and that modulation of the level of dlk expression on stromal cell surfaces can change the growth requirements and differentiation of pre-B cells in contact with them. In vitro, pre-B cells require IL-7 and contact with stromal cells. Removal of IL-7 or stromal cells induces B-lymphocyte differentiation followed by apoptotic cell death. However, interaction with stromal cells with decreased dlk expression, induced by antisense dlk transfection, allows pre-B cell growth in the absence of IL-7. Pre-B cell growth under these conditions is slower than normal, but neither differentiation nor cell death are induced. We also use recombinant oncogenic retroviruses to examine mechanisms responsible for genetic resistance or susceptibility to B-lineage tumor formation. We have demonstrated that pre-B cells from both tumor resistant and tumor susceptible strains can be infected and transformed in vitro by viruses carrrying c-myc with either v-abl or v-raf. These viruses cause B cell tumors in BALB/c mice but not in DBA/2 mice. This suggests that the genetic differences between strains may be external to infected pre-B cells so may include immune surveillance differences. We have also examined the role of oncogene mediated subversion of IL-7 signal transduction and found that, in contrast to abl-myc virus, the raf-myc virus can transform pre-B cells without constitutive activation of IL-7 JAK-STAT signaling. We have also observed that normal in vitro pre-B lines express TGF-beta receptors and are inhibited by exogenous TGF-beta. Pre-B cells transformed by raf-myc maintain this phenotype. In contrast, pre-B cells transformed by abl-myc lose sensitivity to TGF-beta despite continued expression of receptors.