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Effects of human FLT3 ligand on myeloid leukemia cell growth: heterogeneity
in response and synergy with other hematopoietic growth factors
W Piacibello, L Fubini, F Sanavio, MF Brizzi, A Severino, L Garetto, A Stacchini, L Pegoraro and M Aglietta
Department of Biomedical Sciences and Human Oncology, Medical School of
Torino, Italy.
A novel hematopoietic growth factor for primitive hematopoietic progenitor
cells, the ligand for the flt3/flk2 receptor, (FL), has been recently
purified and its gene has been cloned. In the present study, we
investigated the effects of FL on the proliferation and differentiation of
normal and leukemic myeloid progenitor cells. We demonstrate that FL is a
potent stimulator of the in vitro growth of granulocyte-macrophage
colony-stimulating factor (GM-CSF), interleukin- 3 (IL-3), or
G-CSF-dependent granulocyte-macrophage committed precursors from Lin- CD34+
bone marrow cells of normal donors. By contrast, FL does not affect the
growth of erythroid-committed progenitors even in the presence of
erythropoietin. The effect of FL on the proliferation and on the in vitro
growth of clonogenic leukemic precursor cells was studied in 54 acute
myeloid leukemia (AML) cases. Fresh leukemia blasts from 36 of 45 patients
with AML significantly responded to FL without any relation to the
French-American-British (FAB) subtype. FL stimulated the proliferation of
leukemic blasts in a dose-dependent fashion. Synergistic activities were
seen when FL was combined with G-CSF, GM-CSF, IL-3, or stem cell factor
(SCF). FL as a single factor induced or increased significantly colony
formation by clonogenic precursor cells from 21 of 24 patients with AML. In
the presence of suboptimal and optimal concentrations of G-CSF, GM-CSF,
IL3, SCF, or a combination of all factors, FL strongly enhanced the number
of leukemic colonies (up to 18-fold). We also evaluated the induction of
tyrosine phosphorylated protein on FL stimulation in fresh AML cells. We
demonstrate that, on FL stimulation, a band of phosphorylated protein(s) of
about 90 kD can be detected in FL- responsive, but not in FL-unresponsive
cases. This study suggests that FL may be an important factor for the
growth of myeloid leukemia cells, either as a direct stimulus or as a
synergistic factor with other cytokines.
Volume 86,
Issue 11,
pp. 4105-4114,
12/01/1995
Copyright © 1995 by The American Society of Hematology
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