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Editorials
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Figure 1. Schematic summary of the effects of constitutively active RXRA DT448/9PP. (A) Under normal circumstances, the transcriptional activity of RXRA het- erodimerized with other nuclear receptors (NR), including RARA, remains silent, because of co-repressor binding. Selective agonists activate RXRA/NR-driven tran- scription, resulting in cellular differentiation and growth arrest. (B) Mutations of residues 488/9 in RXRA allow potent ligand-independent transcriptional activation and drive differentiation.
ciently in AML.2 In the second study, published last year in Haematologica, di Martino et al. report a serendipitously identified activating mutation in RXRA (RXRA DT448/9PP), which potently activates rexinoid/retinoid downstream signaling and suffices to induce terminal dif- ferentiation of KMT2A-MLLT3-transformed cells.9 The C- terminal helix 12 or AF-2 helix of RXRA, is a critical deter- minant of ligand-dependent transcriptional activity through control of co-activator/co-repressor binding. Surprisingly, di Martino et al. demonstrated that RXRA DT448/9PP overexpression resulted in enhanced tran- scriptional activity leading to multiple features of differen- tiation, notably loss of colony-forming ability, in KMT2A- MLLT3-transformed AML cells. Amazingly, this constitu- tively active RXRA variant binds co-activators completely independently of ligands. Accordingly, transactivation could not be abrogated or further boosted by selective antagonists of RXR or other nuclear receptors, or their agonists, respectively (Figure 1).
These intriguing observations imply that even though rexinoids and retinoids synergize for myeloid differentia- tion of those AML,8 more profound "unconventional" activation by RXRA can initiate terminal differentiation. This master transcriptional regulatory complex deserves further studies to mechanistically decipher how it can become so potent in the absence of ligands. Issues of part- ner proteins, post-translational modifications or non-cod- ing RNA, all come to mind. Whatever the molecular mechanism, these observations suggest that the RXRA/RARA axis, when super-activated, has the poten- tial to initiate terminal differentiation of some AML cells. Further studies should determine which AML exhibit this exquisite sensitivity to RXRA signaling. This re-emerging
theme of retinoid sensitivity in non-APL AML2 could be particularly important in the context of combinations of treatment, particularly with decitabine, as encouraging clinical trials have been published recently,10 with more likely to come.
Disclosures
No conflicts of interest to disclose.
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