Endogenous and combination retinoids are active in myelomonocytic leukemias

Abstract

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.

Cytokine exposure mediates transcriptional activation of the orphan nuclear receptor Nur77 in hematopoietic cells

“…Several differences also are noted in cytokine-dependent effects on UAS/Gal4 reporters. In vitro , Gal4-RARA and Gal4-RXRA are inactive in MLL-AF9 cells grown in IL-3 containing media ( 27 ), whereas Gal4-Nur77 is consistently active ( Fig. 3 ).…”

“…We treated transplanted mice (UAS-GFP x Gal4-Nur77) with granulocyte-colony stimulating factor (G-CSF) to induce granulopoiesis, phenylhydrazine (PHZ) to induce hemolytic anemia, and subsequent erythropoiesis or 5-fluorouracil (5FU) to induce myeloablation and subsequent stem/progenitor expansion. We further evaluated a myeloid malignant stressor, the engraftment of MLL-AF9 leukemia cells ( 27 ). Following these stressors, the mice were sacrificed and reporter activity compared with the mice engrafted under basal conditions.…”

Bexarotene derivatives modify responses in acute myeloid leukemia

“…We had previously observed anti-leukemic synergy between RXRA ligands and RARA ligands. [8] To assess anti-leukemic effects across diverse RXRA compounds, we treated MLL-AF9 leukemia cells with increasing concentrations of each compound in the presence of 100 nM ATRA. Anti-leukemic effects were measured as the total number of viable cells after 5 days across a dose dilution to provide an IC 50 .…”

“…[3, 4, 5, 6] In acute myeloid leukemia (AML) RARA and RXRA have parallel expression among AML subtypes, with highest expression in M4/M5 myelomonocytic and monocytic subtypes. [7, 8]…”

Understanding how retinoic acid derivatives induce differentiation in non- M3 acute myelogeneous leukemia

“…di Martino and colleagues provide exciting new insights into these questions in this issue of Haematologica. 4 …”