Notch1 Perturbation of Hemopoiesis Involves Non-Cell- Autonomous Modifications

To study the effects of Notch on hemopoiesis we used a bone marrow transduction/transplantation model and compared the transduced and nontransduced populations in reconstituted mice. While cells expressing a constitutively active form of murine Notch1 (Notch1IC) completely lacked B cells, a profound suppression of the B lineage was also seen in the nontransduced compartment. Experiments performed with retroviral supernatants of varying titers showed that the perturbations of B cell development among the nontransduced population correlated with the percentage of Notch1IC-transduced cells inoculated into the mice. The myeloid lineage of the Notch1IC-transplanted mice was altered as well, and this also affected the nontransduced population that had features of excessive maturation. To explore the basis of these non-cell-autonomous modifications we prepared conditioned medium from ex vivo cultures of Notch1IC-transplanted mice bone marrow and showed that it inhibited B cell maturation and promoted myeloid differentiation in a dose-dependent manner. Finally, we found that the T cell leukemia/lymphomas that occur in Notch1IC-transplanted mice were accompanied by abnormal maturation of nontransduced T cells in the bone marrow. These findings indicate that modifications of neighboring cells through non-cell-autonomous modifications take part in multiple facets of the activity of Notch on hemopoiesis.