In vitro interaction of recombinant tumor necrosis factor α and all-trans-retinoic acid with normal and leukemic hematopoietic cells

Both human recombinant tumor necrosis factor alpha (TNFα) and all-trans-retinoic acid (RA) inhibit the in vitro clonal growth of human myeloid leukemic cells. We investigated the in vitro interaction of TNFα and RA with normal and a variety of leukemic myeloid cells. With the promyelocytic HL-60 cells, TNFα (≥ 2.5 U/mL) in combination with RA synergistically inhibited clonal growth; TNFα at lower concentrations (≤ 1 U/mL) plus RA (10^-9 mol/L) were antagonistic in their inhibition of growth. The ability of RA (10^-8 mol/L) plus TNFα (2.5, 5 U/mL) to enhance differentiation of HL-60 cells paralleled their ability to inhibit clonal growth of these cells. In addition, RA (10^-9 to 10^-7 mol/L) increased the number of TNFα receptors on HL-60 cells 1.3- to 1.7-fold without changing the affinity for the TNFα receptor. With the more immature KG-1 myeloblasts, concentrations of TNFα > 10 U/mL synergistically interacted with RA to inhibit clonal growth; at lower concentrations of TNFα (< 10 U/mL), RA appeared to inhibit the expected effect of TNFα. KG-1 cells were not induced to differentiate with either agent alone or in combination. With four of nine leukemic patients, TNFα in combination with RA (10^-7 mol/L) inhibited leukemic clonal growth to a greater extent than each agent alone. No marked effect of the combined treatment was seen in two other patients. The RA reversed the inhibitory action of TNFα on normal human granulocyte-macrophage colony forming cells (GM-CFC) and on clonal growth of leukemic cells from three patients. Our study suggests that TNFα and RA interact in a complex manner with normal and leukemic hematopoietic cells.