Regulation of AML2/CBFA3 in hematopoietic cells through the retinoic acid receptor alpha-dependent signaling pathway

AML2 is a member of the acute myelogenous leukemia, AML family of transcrip tion factors, The biologic functions of AML1 and AML3 have been well charac terized; however, the functional role of AML2 remains unknown. In this stud y, we found that AML2 protein expressed predominantly in cells of hematopoi etic origin is a nuclear serine phosphoprotein associated with the nuclear matrix, and its expression is not cell cycle-related. In HL-60 cells AML2 e xpression can be induced by all three natural retinoids, all-trans-retinoic acid (RA), 13-cis-RA, and 9-cis-RA in a dose-dependent manner. A synthetic retinoic acid derivative, 4HPR, which neither activates RA receptor (RAR) alpha nor retinoic X receptor alpha was unable to induce the expression of AML2. A RAR-selective activator,TTNPB, induced AML2 expression similar to R A, Our study further showed that AGN193109, a potent RAR alpha antagonist, suppressed AML2 expression induced by RA and that a retinoic X receptor pan agonist AGN194204 had no effect on its expression, Taken together, these s tudies conclusively demonstrated that the expression of AML2 in HL-60 cells is regulated through the RAR alpha-specific signaling pathway, Our study f urther showed that after all-trans-retinoic acid priming, AML2 expression c ould be augmented by vitamin D-3. Based on these studies we hypothesize tha t AML2 expression is normally regulated by retinoid/vitamin D nuclear recep tors mainly through the RAR alpha-dependent signaling pathway and that it m ay play a role in hematopoietic cell differentiation.