Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation or apoptosis depending on cell culture conditions. Co-repressor release from the RARA:RXRA heterodimer occurred with RARA activation, but not RXRA activation, providing an explanation for the combination synergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved survival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of natural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond acute promyelocytic leukemia.

The retinoid receptors RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in mouse KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with cells treated with the potent RXRA agonist bexarotene, suggestive of constitutive activity that leads to leukemic maturation. Phenotypes of RXRA DT448/9PP appear to differ from two other RXRA mutations with forms of constitutive activity (F318A and S427F), in that DT448/9PP activity was resistant to mutations at critical ligand-interacting amino acids (R316A/L326A) and was resistant to pharmacologic antagonists, suggesting it may be ligand independent. These data provide further evidence that activated RXRs can regulate myeloid maturation and provide a novel constitutively active variant that may be germane for broader studies of RXR in other settings.

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Currently, Adipose-derived Stem Cells (hASCs) therapy is being promoted applied research in the treatment of many diseases, especially autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and type 1 diabetes. However, profound mechanisms of this potential therapy have not been understood entirely. It is questioned that which tissues transplanted cells home to, and how long they survive there?In this work, we evaluated the migration, and survival duration of GFP-expressed hASCs (hASCGFPs) in normal and STZ-induced diabetic mice. A number of 106 hASC-GFPs were intravenous transplanted into the mice. After 1, 3, 5, 7 days, the presence of hASC-GFPs in various organs such as heart, lungs, kidneys, spleen, liver and pancreas was detected by Imaging technique (iBox® ExplorerTM Imaging Microscope System_IMS) and the percentage of these cells in the tissues of diabetic mice was evaluated by Flow cytometry (FCM).The results showed that the transplanted cells could be identified by both IMS and FCM. By IMS, it was clear that hASC-GFPs homed to lung and heart most at day 1 and 3, respectively and the signals were decreased gradually in both tissues. These imaging results were similar in normal and diabetic mice. By FCM, we detected the signals of hASC-GFPs in all six diabetic organs at day 1, 3, 5, 7. The signals expressed highest at day 1 (liver, heart), day 3 (lungs, kidneys, spleen) or day 5 (pancreas) and all gradually decreased until day 7.Our results demonstrated that although difficult hASCs could home to the pancreas of normal as well as diabetic mice, but we need more experiments to make further conclusions regards the mechanism of their immigration and behaviour in the recipients