Interferon-γ enhances growth factor-dependent proliferation of clonogenic cells in acute myeloblastic leukemia

Abstract

Interferon-γ (IFN-γ) 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-γ with recombinant human (rhu) hematopoietic growth factors in the stimulation of clonogenic blasts from most AML patients examined. Under conditions of limiting cell concentration, rhulFN-γ alone showed little effect on blast proliferation, whereas in conjunction with recombinant human interleukin-3 (rhulL-3), IFN-γ significantly enhanced colony formation in 13 of 15 AML cases. Maximal stimulation was obtained at low concentrations of IFN-γ (2 to 20 pmol/L) in four cases and at higher concentrations (700 to 7,000 pmol/L) in the remainder. IFN-γ also synergized with recombinant human granulocytemacrophage colony-stimulating factor (rhuGM-CSF) in 9 of 13 cases. Within 1 hour of exposure, IFN-γ induced a twofold to fourfold accumulation of tumor necrosis factor α (TNFα)-specific transcripts in AML blasts and several AML cell lines that include HL-60 and OCI-AML 1. Further, the synergy between IFN-γ and IL-3 on AML blasts was partially or completely abrogated by a TNFa neutralizing antibody, suggesting that growth enhancement by IFN-γ may be mediated through TNFα 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-γ also resulted in significant growth enhancement, suggesting that the proliferative response elicited by IFN-γ was not limited to AML blasts. Finally, in M07-E, an IL-3-dependent human "megakaryoblastic" cell line, IFN-γ also significantly enhanced IL-3-supported colony formation, much in the same way as in primary AML blasts. In contrast, IFN-γ inhibited growth of all CSF-independent leukemic cell lines tested. This inhibition was partially alleviated by antiTNFα antibody. In summary, our data indicate that IFN-γ can enhance or antagonize cell proliferation, depending on the cell type. Further, TNFα appears to mediate the biologic effect of IFN-γ either in growth stimulation or growth inhibition. © 1997 by The American Society of Hematology.