DNA recognition by the aberrant retinoic acid receptors implicated in human acute promyelocytic leukemia

Human acute promyelocytic leukemias (APLs) are associated with chromosomal translocations that replace the NH2 terminus of wild-type retinoic acid rec eptor (RAR) alpha with portions of the promyelocytic leukemia protein (PML) or promyelocytic leukemia zinc-finger protein (PLZF). The wild-type RAR al pha readily forms heterodimers with the retinoid X receptors (RXRs), and th ese RAR/RXR heterodimers appear to be the principal mediators of retinoid s ignaling in normal cells. In contrast, PML-RAR alpha and PLZF-RAR alpha dis play an enhanced ability to form homodimers, and this enhanced homodimer fo rmation is believed to contribute to the neoplastic properties of these chi meric oncoproteins. We report here that the DNA recognition specificity of the RXR alpha /RAR alpha heterodimer, which is presumed to be the dominant receptor species in normal cells, differs from that of the PML-RAR alpha an d PLZF-RAR alpha homodimers, which are thought to prevail in the oncogenic cell. We suggest that differences in target gene recognition by the normal and oncogenic RAR alpha proteins may contribute to the leukemogenic phenoty pe.