RETINOIC ACID RECEPTOR-ALPHA SUPPRESSES TRANSFORMATION BY V-MYB

Retinoic acid (RA) is capable of inducing the differentiation of vario us myelomonocytic cell lines. During this differentiation process, the levels of c-myb expression decline, suggesting that the RA receptor ( RAR) may act in part by down-regulating this proto-oncogene. We have n ow investigated whether the RAR can also inhibit the function of Myb p roteins themselves. We have found that transcriptional activation of a Myb-responsive reporter gene can be inhibited by RA in a human monocy tic cell line. This inhibition could not be overcome by the expression of exogenous Myb. The RAR did not interfere with DNA binding by Myb p roteins in vitro, suggesting that the functional inhibition occurs at the level of transcriptional activation. To determine the biological r elevance of the inhibition of Myb proteins by the RAR, we have used v- myb-transformed monoblasts. These cells differentiate into macrophages in the presence of phorbol ester (tetradecanoyl phorbol acetate [TPA] ) but are normally unresponsive to RA treatment. The introduction of a n inducible, exogenous RAR alpha into v-myb-transformed monoblasts per mitted an RA-dependent differentiation into macrophage like cells simi lar to those induced by TPA. These results demonstrate that transforma tion by v-myb is recessive to RAR alpha and imply that many types of n on-RA-responsive leukemia cells may become responsive following the in troduction of the RAR.