Effects of TNFalpha on the growth and sensitivity to cytosine arabinoside of blast progenitors in acute myelogenous leukemia with special reference to the role of NF-kappaB.

Leukemic blasts in acute myelogenous leukemia (AML) are derived from a minor population of cells called blast progenitors. Hematopoietic growth factors (HGFs) stimulate their growth and simultaneously sensitize them to cytosine arabinoside (Ara-C), a cell-cycle-specific cytotoxic drug. Since tumor necrosis factor alpha (TNFalpha) modifies HGF activities, we examined the effects of TNFalpha in combination with HGFs on in vitro growth and Ara-C sensitivity of AML blast progenitors in patient samples. TNFalpha variably affected HGF-supported colony formation and the self-renewal of blast progenitors. However, the combination of TNFalpha with IL-3 uniformly rendered blast progenitors more resistant to Ara-C irrespective of whether TNFalpha suppressed or augmented IL-3-supported growth, indicating that TNFalpha regulates the Ara-C sensitivity of leukemic progenitors independently of their cell cycle status. Since nuclear factor-kappaB (NF-kappaB) is activated by TNFalpha and induces expression of prosurvival genes, effects of the antisense oligodeoxynucleotides to NF-kappaB subunits, p65 and p50, were examined. Antisense oligodeoxynucleotides sensitized HL60 cells to Ara-C but rendered leukemic progenitors in patient samples even more resistant to Ara-C in the presence of TNFalpha and IL-3 in combination, indicating that NF-kappaB is involved in the Ara-C sensitivity of leukemic blast progenitors but may exert opposite dual functions, namely protection from and induction of apoptosis, under different conditions.