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Editorials
planted into secondary recipients and reporter activation was used to determine if the leukemias have endoge- neous expression of RXR or RAR ligands. These results show that the AML cells studied have spontaneous acti- vation of RXRA which can be further stimulated with the RXR agonist, bexarotene. In contrast, there is minimal endogeneous activation of RARA. This is consistent with the group’s previous report studying stress myelopoiesis.6 To further study the role of RXRA and RXRB in this AML model the authors planned to induce leukemia in cells engineered to have a deletable form of the receptors. In a case of remarkably informative serendipity, the authors demonstrate robust selection in the leukemias for sponta- neous deletion of RXRA and RXRB. Elegantly designed experiments validate that the RXR complex is a tumor suppressor in this model of AML. This better defines the biology of RXR in AML but targeting of RXR, as further discussed below, has not been adequate to induce a robust response in AML.
However, the authors continue on to studies that inform a pharmacologic approach to treatment of AML. Bexarotene is a small molecular agonist of RXR that Tsai and colleagues previously demonstrated to have modest activity in non-M3 AML.7 diMartino and colleagues con- firm that RXR activity stimulated by bexarotene has in vitro activity decreasing leukemic cell growth and that this is synergistically stimulated by simultaneous activation of RAR using ATRA or the more specific RARA ligand, BMS753.8 They then use the RXRA deleted cells generated in vivo, re-introduce wild type or mutant RXRA and define the domains of RXRA necessary for suppressing leukemo- genesis. This experiment is the most molecular robust def- inition of the requirement for RXR activation to reduce leukemogenesis to date and convincingly demonstrates that bexarotene effects are not off target effects. An inter- esting Figure 4 both validates this conclusion and demon- strates that the effects of retinoid/rexinoid combinations on leukemic cells depend strongly on the cell culture sys- tem. To further define the molecular effects of RAR and RXR on leukemic cells, the authors use reporter assays to show that RARA can have a strong interaction with the nuclear co-repressor, silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Overall, these data suggest that the therapeutic target complex in AML cells is a RARA/RXRA heterodimer which can act as a nuclear repressor. The ATRA-dependent release of co- repressor from the RARA:RXRA heterodimer may account for the synergy described. Simultaneous stimula- tion of both RARA with ATRA and RXR with bexarotene works best to induce this repressive activity and induce leukemic cell death or differentiation.
Importantly, for translational use, diMartino and col- leagues go on to validate efficacy of the drug combination in multiple murine and human models of AML including primary human AML cells studied in culture. The clinical development of this drug combination is challenging. The
authors have used, among other compounds, a bexarotene derivative, CW103-4 which has both RARA and RXRA agonist activity and, in theory, should be a potent anti-leukemic drug. However, CW103-4 is report- ed to be toxic in humans due to the induction of hyper- triglyderidemia.9 Of note, careful experiments shown here confirm that ATRA and bexarotene combinations are quite toxic in mice making it difficult to use the mouse model to test novel rexinoid drug combinations for AML therapy. However, the results here do suggest, for the first time, a way forward in this difficult area. Based on these studies, we can feel confident that the tar- get complex in AML is a RARA: RXRA heterodimer. The therapeutic effects of the ATRA:bexarotene combination is likely achieved through changes in gene expression. Use of the carefully developed murine models shown here should allow for combinations of chromatin immunoprecipitation sequencing (ChiP-seq) and RNA seq studies that may define targets of the drug combina- tion which can be pharmacologically targeted leading to non-toxic differentiation therapy for non-M3 AML. Alternatively, very careful drug binding studies may allow for dissociating the triglyceride regulating effects of retinoids and rexinoids from the myeloid effects. Either one of these approaches may bring us closer to the long- sought goal of differentiation therapy for non-M3 AML.
Disclosures
No conflicts of interest to disclose.
References
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4. di Martino O, Niu H, Hadwiger G, et al. Endogenous and combina- tion retinoids are active in myelomonocytic leukemias. Haematologica. 2021;106(4):1008-1021.
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8. Sanchez PV, Glantz ST, Scotland S, Kasner MT, Carroll M. Induced differentiation of acute myeloid leukemia cells by activation of retinoid X and liver X receptors. Leukemia. 2014;28(4):749-760.
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