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

Joseph J. Dolence, Kimberly Gwin, Elena Frank, Kay L. Medina

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)324-334
Number of pages11
JournalEuropean Journal of Immunology
Volume41
Issue number2
DOIs
StatePublished - Feb 1 2011

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Keywords

  • Apoptosis
  • B-cell development
  • Cell differentiation
  • Flt3-ligand

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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