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Interferon-gamma enhances growth factor-dependent proliferation of
clonogenic cells in acute myeloblastic leukemia
I Murohashi and T Hoang
Laboratory of Hemopoiesis and Leukemia, Clinical Research Institute of
Montreal, Quebec, Canada.
Interferon-gamma (IFN-gamma) has been reported to antagonize the
stimulatory effect of various conditioned media on the growth of normal
hematopoietic progenitor cells and clonogenic blasts from patients with
chronic myelogenous leukemia (CML) and acute myeloblastic leukemia (AML).
In the present study, using purified recombinant cytokines and homogenous
cell populations, we provide evidence for a synergistic or additive effect
of IFN-gamma with recombinant human (rhu) hematopoietic growth factors in
the stimulation of clonogenic blasts from most AML patients examined. Under
conditions of limiting cell concentration, rhuIFN-gamma alone showed little
effect on blast proliferation, whereas in conjunction with recombinant
human interleukin-3 (rhuIL-3), IFN- gamma significantly enhanced colony
formation in 13 of 15 AML cases. Maximal stimulation was obtained at low
concentrations of IFN-gamma (2 to 20 pmol/L) in four cases and at higher
concentrations (700 to 7,000 pmol/L) in the remainder. IFN-gamma also
synergized with recombinant human granulocyte-macrophage colony-stimulating
factor (rhuGM-CSF) in 9 of 13 cases. Within 1 hour of exposure, IFN-gamma
induced a twofold to fourfold accumulation of tumor necrosis factor alpha
(TNF alpha)- specific transcripts in AML blasts and several AML cell lines
that include HL-60 and OCI-AML 1. Further, the synergy between IFN-gamma
and IL-3 on AML blasts was partially or completely abrogated by a TNF alpha
neutralizing antibody, suggesting that growth enhancement by IFN-gamma may
be mediated through TNF alpha production in AML blast culture. Exposure of
normal precursors (burst-forming unit-erythroid [BFU-E] and colony-forming
unit granulocyte-macrophage [CFU-GM]) to IFN-gamma also resulted in
significant growth enhancement, suggesting that the proliferative response
elicited by IFN-gamma was not limited to AML blasts. Finally, in M07-E, an
IL-3-dependent human "megakaryoblastic" cell line, IFN-gamma also
significantly enhanced IL-3-supported colony formation, much in the same
way as in primary AML blasts. In contrast, IFN-gamma inhibited growth of
all CSF-independent leukemic cell lines tested. This inhibition was
partially alleviated by anti-TNF alpha antibody. In summary, our data
indicate that IFN-gamma can enhance or antagonize cell proliferation,
depending on the cell type. Further, TNF alpha appears to mediate the
biologic effect of IFN-gamma either in growth stimulation or growth
inhibition.
Volume 78,
Issue 4,
pp. 1085-1095,
08/15/1991
Copyright © 1991 by The American Society of Hematology
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