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Synergy between all-trans retinoic acid and tumor necrosis factor pathways in acute leukemia cells

Synergy between all-trans retinoic acid and tumor necrosis factor pathways in acute leukemia cells,Michael Witcher,Douglas T. Ross,Caroline Rousseau,L

Synergy between all-trans retinoic acid and tumor necrosis factor pathways in acute leukemia cells   (Citations: 24)
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The nuclear receptor ligand all-trans reti- noic acid (ATRA) causes dramatic termi- nal differentiation of acute promyelocytic leukemia (APL) cells in vitro and in pa- tients, but it is less active in other malig- nancies. However, downstream media- tors of the effects of ATRA are not well understood. We used a cDNA microarray to search for ATRA-regulated genes in the APL cell line NB4 and found that ATRA regulated several members of the tumor necrosis factor (TNF) pathway. Here we show that TNF can synergize with ATRA to induce differentiation, showing mono- cytic characteristics more typical of differ- entiation mediated by TNF than by ATRA. ATRA and TNF can also induce differentia- tion of the non-APL cell line U937. Under- lying this response was an increase in TNF-induced nuclear factor- (NF-) DNA binding within 2 hours in the pres- ence of ATRA and activation of NF- DNA binding and transcriptional activity in response to ATRA alone within 48 hours of ATRA treatment. Furthermore, we found a synergistic induction of the NF- target genes BCL-3, Dif-2, and TNF receptor 2 (TNFR2) in response to the combination of TNF and ATRA. These genes have been previously shown to play a role in TNF signaling, and amplifica- tion of such genes may represent a mechanism whereby TNF and ATRA can act synergistically. We propose that ATRA can prime cancer cells for differentiation triggered by TNF and suggest that target- ing the TNF pathway in combination with ATRA may represent a novel route to treat leukemias. (Blood. 2003;102:237-245)
Published in 2003.
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