TY - JOUR
T1 - Flt3 signaling regulates the proliferation, survival, and maintenance of multipotent hematopoietic progenitors that generate B cell precursors
AU - Dolence, Joseph J.
AU - Gwin, Kimberly A.
AU - Shapiro, Mariya B.
AU - Medina, Kay L.
N1 - Funding Information:
We thank Virginia Smith Shapiro for helpful discussions and critical comments on the manuscript, and the Mayo Clinic Flow Cytometry Core Facility for technical expertise. This work was supported by National Heart, Lung, and Blood Institute grant R01HL096108 (to K.L.M.) and National Institutes of Health training grant T32AI07425 to the Department of Immunology (to J.J.D.)
PY - 2014/5
Y1 - 2014/5
N2 - Flt3 signaling plays a crucial role in regulating the survival and differentiation of lymphoid progenitors into B cell precursors (BCPs) in bone marrow. To define further 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 with flt3l-/- mice, Eμ-bcl2tg flt3l-/- mice had significantly increased multipotential progenitors (MPPs), IL-7R+ common lymphoid progenitors, and B cell precursors. To determine whether 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 effect on lymphoid priming before 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, but not Flt3+ B lymphoid progenitors (BLPs), the immediate precursors of BCPs. BCPs were restored after temporal invivo FL treatment, albeit with delayed kinetics. Together, these results show that Flt3 regulates the proliferation, survival, and maintenance of developmental stage-specific hematopoietic progenitors that give rise to BCPs.
AB - Flt3 signaling plays a crucial role in regulating the survival and differentiation of lymphoid progenitors into B cell precursors (BCPs) in bone marrow. To define further 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 with flt3l-/- mice, Eμ-bcl2tg flt3l-/- mice had significantly increased multipotential progenitors (MPPs), IL-7R+ common lymphoid progenitors, and B cell precursors. To determine whether 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 effect on lymphoid priming before 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, but not Flt3+ B lymphoid progenitors (BLPs), the immediate precursors of BCPs. BCPs were restored after temporal invivo FL treatment, albeit with delayed kinetics. Together, these results show that Flt3 regulates the proliferation, survival, and maintenance of developmental stage-specific hematopoietic progenitors that give rise to BCPs.
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U2 - 10.1016/j.exphem.2014.01.001
DO - 10.1016/j.exphem.2014.01.001
M3 - Article
C2 - 24444745
AN - SCOPUS:84901033608
SN - 0301-472X
VL - 42
SP - 380-393.e3
JO - Experimental Hematology
JF - Experimental Hematology
IS - 5
ER -