The key pathogenesis of leukemia is the defection of the differentiation processes of hematopoietic stem cells. There are five APRO (anti-proliferative) genes, BTG1, BTG2, BTG3, TOB and TOB2, and it was reported that certain APRO genes are associated with cell differentiation. However, it is still unknown whether APRO genes are related with the differentiation process of blood cells. In this study, we investigated the expression of APRO genes in 12-O-tetra-decanoylphorbol-13-acetate (TPA) or retinoic acid (RA)-treated HL-60 cell lines. Our data show that the expression of the BTG2 gene was increased in 32 nM TPA-treated and 1 microM RA-treated HL-60 cells, but the expression of the BTG1 and BTG3 genes was not increased. The expression of BTG2 in TPA- or RA-treated HL-60 cells was also increased even in the presence of cyclohexamide, which is an inhibitor of translation, implying that the increased expression of BTG2 mRNA did not require the new synthesis of another protein. Notably, the up-regulation of BTG2 in TPA- or RA-treated HL-60 cells was observed prior to the increased expression of p21. Our data show that PKC pathways are uninvolved with the up-regulation of BTG2 in TPA- or RA-treated HL-60 cells. Thus, the up-regulation of BTG2 genes may be involved in the differentiation process of HL-60 cells after TPA or RA treatment. Furthermore, this event occurred prior to p21 expression, implying that the BTG2 expression plays a role at a very early point during the differentiation processes of hematopoietic cells.