Results from two new studies provide mechanistic insights into the molecular events that cause acute promyelocytic leukemia (APL). APL is a a cancer of the bone marrow that occurs when certain developing white blood cells get stuck at a highly proliferative and immature stage.
Researchers from The Institute of Cancer Research and Baylor College of Medicine characterized the transformation mechanisms involved in APL. To do this they functionally separated homodimerization and the intrinsic DNA-binding properties of RARA (retinoic acid receptor alpha) fusion proteins from transformation of primary blood cells.
The researchers say that they found homodimerization was not sufficient for RARA fusion-mediated transformation, but higher-order RXRA/RAR fusion hetero-oligomeric complexes that aberrantly recruit transcriptional corepressors to downstream targets were essential. Disruption of retinoid X receptor (RXR)-dependent pathways suppressed RARA fusion-mediated transformation. The authors also suggest that disruption of homotetramers into homodimers may be sufficient to abrogate the transformation ability of RARA fusion proteins.
A separate group from CNRS investigated the role of RXR in the PML (promyelocytic leukemia) /RARA complex through a variety of experiments. They found that although RXR was not required for transformation of blood cells in primary culture, it was absolutely essential for APL development in PML/RARA transgenic mice. Pharmacological activation of RXR relieved PML/RARA-induced transcriptional repression and triggered APL differentiation only when RXR was in a complex with PML/RARA.
In addition, PML/RARA promoted post-translational modifications of RXR, including its sumoylation, a modification that triggers transcriptional repression for RXR, and many other transcription factors.
"The presence of RXR in the PML/RARA complex not only greatly facilitates DNA binding but is also required for rexinoid-induced differentiation, demonstrating that RXR is not a silent partner but a critical determinant of transformation," explains Hugues de Thé, M.D., Ph.D., leader of the this study. “In addition, our observations suggest that dysregulated sumoylation induced by PML/RARA may contribute to altered gene expression and APL pathogenesis.”
Taken together, results from these studies indicate that formation of higher-order homotetrameric complexes and recruitment of RXR are essential components of RARA-induced transformation. It also shows that that RXR is a key member of the PML/RARA-associated oncogenic response that facilitates PML/RARA-induced transformation through multiple mechanisms and participates in the differentiation response, according to the scientists.
The research is published in the July issue of Cancer Cell.