Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells

To elucidate the molecular mechanism of all-trans-retinoic acid (ATRA)-indu ced differentiation of acute promyelocytic leukemia (APL) cells, the gene e xpression patterns in the APL cell line NB4 before and after ATRA treatment were analyzed using complementary DNA array, suppression-subtractive hybri dization, and differential-display-polymerase chain reaction. A total of 16 9 genes, including 8 novel ones, were modulated by ATRA. The ATRA-induced g ene expression profiles were in high accord with the differentiation and pr oliferation status of the NB4 cells. The time courses of their modulation w ere interesting. Among the 100 up-regulated genes, the induction of express ion occurred most frequently 12-48 hours after ATRA treatment, while 59 of 69 down-regulated genes found their expression suppressed within 8 hours. T he transcriptional regulation of 8 induced and 24 repressed genes was not b locked by cycloheximide, which suggests that these genes may be direct targ ets of the ATRA signaling pathway. A balanced functional network seemed to emerge, and it formed the foundation of decreased cellular proliferation, m aintenance of cell viability, increased protein modulation, and promotion o f granulocytic maturation. Several cytosolic signaling pathways, including JAKs/STAT and MAPK, may also be implicated in the symphony of differentiati on. (Blood. 2000;96:1496-1504) (C) 2000 by The American Society of Hematolo gy.