FLT3 LIGAND SUPPORTS THE DIFFERENTIATION OF EARLY B-CELL PROGENITORS IN THE PRESENCE OF INTERLEUKIN-11 AND INTERLEUKIN-7

B cell development is influenced by interactions between B cell progen itors and stromal cells. The precise mechanisms by which these interac tions regulate B cell differentiation are currently unknown. Flt3 liga nd (FL) is a growth factor which stimulates the proliferation of stem cells and early progenitors. Mice deficient for the FLT3 receptor exhi bit severe reductions in early B lymphoid progenitors. We have previou sly described a clonal assay in vitro which allows us to follow the en tire B cell differentiation pathway from uncommitted progenitors to ma ture, immunoglobulin-secreting plasma cells. The growth factor combina tion of interleukin (IL)-11, mast cell growth factor (MGF) and IL-7 wa s shown to maintain the differentiation of these hematopoietic precurs ors into B cell progenitors capable of giving rise to functionally mat ure B cells in secondary cultures. Here, we show that FL in combinatio n with IL-11 and IL-7 is sufficient to support the differentiation of uncommitted progenitors from day 10 yolk sac (AA4.1(+)) or day 12 feta l liver (AA4.1(+) B220(-) Mac-1(-) Sca-1(+)) into the B lineage. The f requency of B cell progenitors obtained in these conditions was simila r, if not better, than the frequency of B cell precursors that arose w hen cultured in IL-11+MGF+IL-7. Furthermore, the growth factor combina tion of IL-11+FL+IL-7 was able to maintain the potential of bipotent p recursors giving rise to both the B and myeloid lineages in secondary cultures. We also show that FL synergizes with IL-7 in the proliferati on of committed B220(+) pro-B cells and may contribute to the maintena nce of an earlier pro-B cell population. Together, these results show that FL is important in supporting the differentiation and proliferati on of early B cell progenitors in vitro.