Recruitment of RXR by Homotetrameric RARα Fusion Proteins Is Essential for Transformation

Summary While formation of higher-order oncogenic transcriptional complexes is critical for RARα fusion proteins in acute promyelocytic leukemia, the essential components and their roles in mediating transformation are still largely unknown. To this end, the present study demonstrates that homodimerization is not sufficient for RARα fusion-mediated transformation, which requires higher-order homotetramerization. Surprisingly, intrinsic homo-oligomeric DNA binding by the fusion proteins is also dispensable. Importantly, higher-order RXR/RARα fusion hetero-oligomeric complexes that aberrantly recruit transcriptional corepressors to downstream targets are essential for transformation. Intervention of RXR-dependent pathways by panRXR-agonists or RXRα shRNAs suppresses RARα fusion-mediated transformation. Taken together, these results define the oncogenic threshold for self-association and reveal the pathological significance of higher-order RARα fusion/RXR hetero-oligomeric complexes and their potential value as a therapeutic target.