Self-renewal and differentiation of stem cells in a biopotential murine
leukemia: an in vitro model for differentiation therapy
U Duhrsen, G Knieling, HX Wu and DK Hossfeld
Abteilung fur Onkologie und Hamatologie, Universitatskrankenhaus Eppendorf,
Hamburg, Germany.
PGM-2 is a variant of the transplantable PGM-1 leukemia of strain C3H/HeJ.
Freshly explanted cells had lymphoid morphology with a CD5+ CD45R (B220)-
IgM- phenotype. They were not viable in unstimulated cultures, but formed
IgM+ lymphoid colonies in response to interleukin- 2 (IL-2), IL-4, IL-5,
IL-6, IL-7, and Steel factor, and macrophage colonies in response to IL-3.
IL-3-stimulated colonies had no recloning potential, but colonies from IL-7
cultures gave rise to large numbers of secondary macrophage colonies in
IL-3-stimulated cultures and secondary lymphoid colonies in IL-7-stimulated
cultures. The latter ones could be serially transferred in vitro for
several months, and formed typical PGM-2 tumors in vivo. IL-7-stimulated
colonies could therefore be used to measure leukemic stem cells in vitro.
Supramaximal IL-3 stimulation (2,500 U/mL) of suspension cultures was
followed by an increase in overall cell numbers and a disappearance of
leukemic stem cells, compatible with differentiation induction. This could
not be counteracted by simultaneous stimulation with IL-7. However, lower
IL-3 concentrations (500 U/mL) induced an expansion of the stem cell pool,
possibly by facilitating density-dependent autostimulatory mechanisms
involving endogenous production of IL-7. The system described is a simple
in vitro model for differentiation therapy. It shows that leukemic stem
cells can be induced by hematopoietic growth factors to undergo terminal
differentiation, but the concentrations required for differentiation
induction in stem cells are much higher than those required for other
biologic effects. Submaximal stimulation may favor expansion rather than
repression of the leukemic cell population.
Volume 83,
Issue 9,
pp. 2627-2636,
05/01/1994
Copyright © 1994 by The American Society of Hematology
