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FLT-3 Ligand and Marrow Stroma-Derived Factors Promote CD3 ,
CD3 , CD3 , and RAG-2 Gene Expression in Primary Human
CD34+LIN DR Marrow
Progenitors
Patrick M. Gaffney,
Jeanne Lund, and
Jeffrey S. Miller
From the Department of Medicine, University of Minnesota Cancer
Center, Minneapolis.
We hypothesize that early lymphoid commitment from primitive
hematopoietic marrow progenitors is governed by signals from the marrow
microenvironment leading to sequential induction of lineage-specific
genes. Using expression of lymphoid genes as markers of
differentiation, we characterize a highly purified population
(>99.8% by double sorting) of primary human
CD34+Lin DR progenitors.
This population was then used to evaluate the effects of supplemental
cytokines (interleukin-2 [IL-2], IL-3, IL-7, c-kit ligand),
FLT-3 ligand (FL), and stroma-derived factors on
lymphoid differentiation in vitro. CD3 , RAG-1, Ikaros, CD10, and TdT
transcripts were detected in the starting
CD34+LinDR population. By
contrast, CD3 , CD3 , CD3 , and RAG-2 transcripts were not
present in any samples tested. The presence of supplemental cytokines
alone at culture initiation permitted stimulation of the expression of
CD3, but not of CD3 or CD3. However, when FL and
stroma-derived factors were added to cytokines, CD3 gene expression was
induced in all samples. The predominant CD3 transcripts induced by
optimal culture conditions were alternatively spliced isoforms lacking
transmembrane sequences (CD3 and CD3) and portions of the
intracellular and extracellular domains (CD3). The combination of
cytokines, FL, and stromal factors also provided a potent stimulus for
RAG-2 gene expression. These findings show that FL in combination with
stroma-derived factors provide important signals to promote early
events required for lymphoid differentiation.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1662-1670
© 1998 by The American Society of Hematology.
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