DOI:10.1038/nrc2214 It is well established that the fusion

of retinoic acid receptor α (RARα) with another protein that promotes self association is implicated in the pathogenesis of acute promyelocytic leukaemia (APL). Treatment based on targeting RARα is effective for many patients; however, some patients do not respond or become resistant to this treatment. Two papers now show that retinoid X receptor α (RXRα) has an essential role in different models of APL, indi-cating new therapeutic avenues.

RARα fusion proteins form homodimers, and these can in turn form tetra- or oligomeric complexes. In addition, heteromeric complexes that include RXRα are also formed, and targeting RXRα can reduce the oncogenic effect of PML–RARα. However, the specific effects that these different complexes have on APL development remain unclear. To address this, Bernd Zeisig and colleagues focused on a rare RARα fusion protein, STAT5b–RARα (SR), that was initially cloned from a patient with APL. Gel-filtration analyses showed that deletion of the N-terminal (∆N) homotetrameriza-tion domain or loss of the coiled-coil (∆CC) homodimerization domain in the STAT5b half of SR resulted in a loss of homo-oligomeric forms. ∆CC mutants were still able to form homotetramers, but ∆N mutants only formed homodimers, and were unable to transform haematopoietic cells in vitro. Because the oncogenic effect of RARα fusion proteins relies on DNA binding, the authors examined whether this was compro-mised in the mutants. Both SR-∆N and surprisingly SR-∆CC showed reduced DNA binding, despite the fact that SR-∆CC can transform

cells. Furthermore, homo-oligomer-ized RARα fusion proteins did not bind DNA efficiently, even though they also transform cells in vitro. These results indicate that intrinsic homo-oligomeric DNA binding is not crucial for transformation by RARα fusion proteins in vitro. Heterodimerization with RXRα was essential for efficient DNA binding, and for interactions with chromatin modifiers that mediate RARα fusion protein suppression of RARα target gene expression. Moreover, disrup-tion of RXRα function suppresses RARα fusion protein transformation. The authors conclude that drugs that target RXRα or that could reduce RARα fusion protein complexes to homodimers are potential future treatments for APL.

Jun Zhu and colleagues have also investigated the function of RXRα in APL. They looked at the more common fusion between PML and RARα. RXRα is known to be present in the PML–RARα complex, so these authors made a PML–RARα mutant that is unable to bind RXRα, but can still form homo-oligomeric complexes. Interestingly, they found that this mutant can transform primary haematopoietic cells in vitro, but that it cannot cause APL in vivo. Instead, mice that express the mutant PML–RARα develop a myelopro-liferative-like disease that has so far never progressed to APL. Both wild-type and mutant PML–RARα can bind DNA in vitro, indicating that RXRα is not essential for DNA binding. However, despite the ability of the mutant to bind DNA in vitro, only wild-type PML–RARα was able to induce the suppression of RARα target genes in vivo. These authors further showed that the binding

of RXRα to PML–RARα results in post-translational modification of RXRα, notably its sumoylation. Therefore, PML–RARα might enable the localization of active sumoylation machinery near PML–RARα bind-ing sites, thus sumoylating RXRα and chromatin-regulatory proteins, which might alter their function.

Both papers indicate that a greater understanding of the functional interactions of RAR fusion proteins, both in vitro and in vivo, is required to identify new therapeutic targets for this disease.

Nicola McCarthy

OrIgInal research PaPers Zeisig, B. B. et al. Recruitment of RXR by heterotetrameric RARα fusion proteins is essential for transformation. Cancer Cell 12, 36–51 (2007) | Zhu, J. et al. RXR is an essential component of the oncogenic PML/RAR complex in vivo. Cancer Cell 12, 23–35 (2007)

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Xceptional target?

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NATuRe RevIewS | cancer voLuMe 7 | SePTeMBeR 2007

Nature Reviews Cancer | AoP, published online 9 August 2007; doi:10.1038/nrc2214

© 2007 Nature Publishing Group