LYMPHOHEMATOPOIETIC PROGENITORS IMMORTALIZED BY A RETROVIRAL VECTOR HARBORING A DOMINANT-NEGATIVE RETINOIC ACID RECEPTOR CAN RECAPITULATE LYMPHOID, MYELOID, AND ERYTHROID DEVELOPMENT

The lymphohematopoietic progenitors represent <0.01% of nucleated marr ow cells. Here, we describe the immortalization of the murine lymphohe matopoietic progenitors by a retroviral vector harboring a dominant-ne gative retinoic acid receptor. The immortalized progenitors proliferat e as a stem-cell-factor-dependent clonal line EML that spontaneously g enerates pre-pro-B lymphocytes and erythroid and myeloid progenitors. Upon stimulation with interleukin-7 and stromal cells, the pre-pro-B l ymphocytes express RAG-1 and undergo D-J rearrangements of the immunog lobulin heavy-chain genes. With erythropoietin the erythroid progenito rs proliferate and differentiate into red cells. Generation of the com mon progenitors for neutrophils and macrophages is suppressed in EML b ut is inducible by high concentrations of retinoic acid. An additional block in neutrophil differentiation occurs at the promyelocyte stage but can also be overcome by high concentrations of retinoic acid. Thes e studies demonstrate a reproducible way to immortalize lymphohematopo ietic progenitors and implicate specific roles for retinoic acid recep tors at two distinct stages of hematopoiesis.