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Threshold levels of Flt3‐ligand are required for the generation and survival of lymphoid progenitors and B‐cell precursors

The generation of B‐cell precursors (BCP) from lymphohematopoietic progenitors (LHP) in bone marrow is dependent on signals provided by the receptor tyrosine kinase Flt3 and its ligand, Flt3‐ligand (FL). Mice deficient in FL exhibit striking reductions in LHP and BCP. Currently, the mechanism by which Flt3 regulates lymphoid lineage/B‐cell development is unknown. Here, we show that haploinsufficiency of FL (FL+/−) reduced the numbers of LHP, common lymphoid progenitors, and pro‐B cells, suggesting that FL levels set a threshold for B lymphopoiesis. Limiting dilution analysis confirmed reduced BCP frequency in FL+/− mice. Real‐time PCR of LHP from FL+/− animals showed increased transcripts of the B lineage inhibitor id1. However, targeted deletion of id1 did not restore the lymphoid/B lineage deficiencies in FL−/− mice, supporting Id1‐independent mechanisms. BrdU incorporation studies established that FL is not essential for the proliferation of Flt3+ multipotential progenitors. Analysis of FL−/− progenitors expressing low levels of Flt3 revealed decreased levels of the pro‐survival factor Mcl1. Consequently, the Flt3+ LHP progeny of Flt3low LSK+ cells exhibited increased Annexin V staining. Together, these data suggest that Flt3 signaling initiates a cascade of events in Flt3low precursors that promote the survival of LHP from which BCP are derived.