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Flt3 signaling regulates the proliferation, survival, and maintenance of multipotent hematopoietic progenitors that generate B cell precursors

Authors
  • Dolence, Joseph J.
  • Gwin, Kimberly A.
  • Shapiro, Mariya B.
  • Medina, Kay L.1, 2, 3, 2
  • 1 Department of Immunology
  • 2 Mayo Clinic College of Medicine
  • 3 Mayo Graduate School
Type
Published Article
Journal
Experimental Hematology
Publisher
Elsevier
Publication Date
Jan 01, 2014
Accepted Date
Jan 02, 2014
Identifiers
DOI: 10.1016/j.exphem.2014.01.001
Source
Elsevier
Keywords
License
Unknown

Abstract

Flt3 signaling plays a crucial role in regulating the survival and differentiation of lymphoid progenitors into B cell precursors (BCP) in bone marrow (BM). To further define the role of Flt3 signaling in lymphoid progenitor survival, mice deficient in Flt3 ligand that also expressed a Bcl2 transgene (Eμ-bcl2tg flt3l-/-) were generated. Intracellular flow cytometry established transgene expression in primitive hematopoietic progenitors, including Lineage-negative Sca-1+ c-kit+ (LSK+) CD27- cells enriched for functional hematopoietic stem cells. Compared to flt3l-/- mice, Eμ-bcl2tg flt3l-/- mice had significantly increased multipotential progenitors (MPPs), IL-7R+ common lymphoid progenitors (CLP), and B cell precursors. To determine if forced expression of Bcl2 was sufficient to restore lymphoid priming in the absence of Flt3 signaling Eμ-bcl2tg flt3l-/- rag1-gfp+ mice were generated. Analysis of Eμ-bcl2tg flt3l-/- rag1-gfp+ mice revealed that the Bcl2 transgene had no impact on lymphoid priming prior to CD19 expression. Thus, forced expression of a survival gene can bypass the requirement for threshold levels of Flt3 signaling requisite for lymphoid priming. Temporal Flt3 ligand (FL) replacement therapy in flt3l-/- mice revealed specific requirements for Flt3 signaling in the expansion and maintenance of Flt3+hi MPP and Flt3+ all lymphoid progenitors (ALPs), but not Flt3+ B lymphoid progenitors (BLPs), the immediate precursors of BCP. BCP were restored after temporal in vivo FL treatment, albeit with delayed kinetics. Together, these results show that Flt3 regulates the proliferation, and survival, and maintenance of developmental-stage-specific hematopoietic progenitors that give rise to BCP.

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