We have been studying molecular mechanisms governing lymphoid cell differentiation and neoplasia. We have discovered a role for dlk in cell-cell interactions during differentiation of B-lymphocytes and adipocytes. Dlk is a member of the EGF-like homeotic gene family which influence cell fate during development. Dlk controls adipocyte differentiation and mediates its effect through cell-cell contact. Downregulation of dlk is necessary for adipocyte differentiation. 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 normally require IL-7 and contact with bone-marrow derived 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. Recombinant retroviruses carrying two oncogenes, either v-abl and c-myc or v-raf and v-myc, cause B cell tumors in BALB/c mice but do not give B cell tumors when injected into DBA/2 mice. In contrast, we have demonstrated that pre-B cells from both tumor resistant and tumor susceptible strains can be infected and transformed by virus in vitro. 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.
NIH ExPorter
NIH ExPorter