Retinoic acid (RA) signaling pathways regulate fundamental biological processes, such as cell proliferation, development, differentiation, and apoptosis. Retinoid receptors (RARs and RXRs) are ligand-dependent transcription factors. All-trans retinoic acid (ATRA) is the principal endogenous ligand for the retinoic acid receptor alpha (RARA) and is produced by the enzymatic oxidation of dietary vitamin A, whose deficiency is associated with several pathological conditions. Differentiation therapy using ATRA revolutionized the outcome of acute promyelocytic leukemia (APL), although attempts to replicate these results in other cancer types have been met with more modest results. A better knowledge of RA signaling in different leukemia contexts is required to improve initial designs. Here, we will review the RA signaling pathway in normal and malignant hematopoiesis, and will discuss the advantages and the limitations related to retinoid therapy in acute myeloid leukemia.

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.

Background: YB-1 is a multifunctional protein that affects transcription, splicing, and translation. Results: ⌬Np63␣, the main p63 protein isoform, interacts with YB-1 and affects YB-1 subcellular localization and regulation of cell survival and motility genes. Conclusion: ⌬Np63␣ and YB-1 interaction inhibits epithelial to mesenchymal transition and tumor cell motility. Significance: This is the first demonstration of a physical and functional interaction between YB-1 and ⌬Np63␣ oncoproteins.

Cutaneous squamous cell carcinomas (SCCs) typically lack somatic oncogene-activating mutations and most of them contain p53 mutations. However, the presence of p53 mutations in skin premalignant lesions suggests that these represent early events during tumor progression and additional alterations may be required for SCC development. SCC cells frequently express high levels of ΔNp63α and Y-box binding 1 (YB-1 or YBX1) oncoproteins. Here, we show that knockdown of YB-1 in spontaneously immortalized HaCaT and non-metastatic SCC011 cells led to a dramatic decrease of ΔNp63α, cell detachment and death. In highly metastatic SCC022 cells, instead, YB-1 silencing induces PI3K/AKT signaling hyperactivation which counteracts the effect of YB-1 depletion and promotes cell survival. In summary, our results unveil a functional cross-talk between YB-1, ΔNp63α and the PI3K/AKT pathway critically governing survival of squamous carcinoma cells.

The retinoid X receptor α (RXRA) has been implicated in diverse hematological processes. However, it is unknown whether natural ligands of RXRA are present in hematopoietic cells. We adapted our upstream activation sequence-green fluorescent protein (UAS-GFP) reporter mouse to detect natural RXRA ligands in vivo. We observed reporter activity in diverse, primary mouse hematopoietic cells in vivo. We found that reporter activity increased during granulocyte colony stimulating factor (GCSF)–induced granulopoiesis and following phenylhydrazine (PHZ)–induced anemia, suggesting the presence of dynamically regulated natural RXRA ligands in hematopoietic cells. We found that mouse plasma could activate Gal4-UAS reporter cells in vitro, and plasma from mice treated with GCSF and PHZ recapitulated the patterns we observed in vivo. Severe vitamin A depletion had only a mild effect on RXRA reporter activity, whereas short-term fatty acid restriction reduced reporter activity, implicating fatty acids as plasma RXRA ligands. Through differential extraction, coupled with mass spectrometry, we identified the long chain fatty acid C24:5 as a natural RXRA ligand, which was dynamically increased in concentration in response to hematopoietic stress. Collectively, these data demonstrate that natural RXRA ligands are present and are dynamically increased in vivo in mouse hematopoietic cells.