Retinoic acid (RA) induces the in vitro granulocytic differentiation of the HL-60 promyelocytic leukemia cell line and is a potentially attractive alternative therapeutic agent for the treatment of acute myelogenous leukemia (AML) particularly of the promyelocytic (M3) variety. Nevertheless, the therapeutic efficacy of RA is severely limited by the fact that it does not induce differentiation of most other types of AML cells. Utilizing retroviral-mediated gene transduction we have determined that the retinoic acid receptor alpha (RAR-alpha), a member of the steroid/thyroid hormone receptor superfamily of nuclear transcription factors, plays a critical and central role in mediating RA-induced granulocytic differentiation of HL-60 cells. Paradoxically, however, most myeloid leukemia cells, including those that are clearly RA-unresponsive, also express RA receptor alpha mRNA. We wish to determine whey some AML cells are sensitive to RA-induced terminal differentiation while most others are not. We will determine whether RA-resistant myeloid leukemias exhibit structural and functional abnormalities in the RA receptor itself, harbor other factors such as thyroid hormone receptors or """"""""dominant negative"""""""" RA receptor mutations which may negatively regulate the activity of normal RA receptors, or exhibit differences in molecular events occurring """"""""downstream"""""""" of RA receptor activation. We will also assess the tissue specific activity of the different RA receptors (RAR- alpha, beta, gamma and RXR-alpha) in hematopoietic cells. These studies should help determine the molecular basis for both RA-induced differentiation and RA- resistance of myeloid leukemia cells. Moreover, the studies on thyroid hormone-retinoic acid receptor interaction should provide considerable insight into the role these important transcription factors play in hematopoietic cell growth and differentiation.
