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DNA Recognition by the Aberrant Retinoic Acid Receptors Implicated in Human Acute Promyelocytic Leukemia¹

Section of Microbiology, Division of Biological Sciences, University of California at Davis, Davis, California 95616

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

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