Retinoid differentiation therapy for common types of acute myeloid leukemia

Abstract

Many cancers arise in a tissue stem cell, and cell differentiation is impaired resulting in an accumulation of immature cells. The introduction of all-trans retinoic acid (ATRA) in 1987 to treat acute promyelocytic leukemia (APL), a rare subtype of acute myeloid leukemia (AML), pioneered a new approach to obtain remission in malignancies by restoring the terminal maturation of leukemia cells resulting in these cells having a limited lifespan. Differentiation therapy also offers the prospect of a less aggressive treatment by virtue of attenuated growth of leukemia cells coupled to limited damage to normal cells. The success of ATRA in differentiation therapy of APL is well known. However, ATRA does not work in non-APL AML. Here we examine some of the molecular pathways towards new retinoid-based differentiation therapy of non-APL AML. Prospects include modulation of the epigenetic status of ATRA-insensitive AML cells, agents that influence intracellular signalling events that are provoked by ATRA, and the use of novel synthetic retinoids.

Figure 1

Influence of inhibiting the activity of AKR1C3 on PGD₂ metabolism. Inhibiting the activity of AKR1C3 by the use of indomethacin or medroxyprogesterone acetate (MPA) interferes with prostaglandin D₂ (PGD₂) metabolism towards 9α,11β PGF₂ and favours nonenzymatic metabolism towards J-series prostanoids and the PPARγ ligand 15-deoxy-Δ12,14-PGJ₂.

Figure 2

Inhibition of the activity of GSK-3β is important for ATRA sensitivity, The figure shows one way in which activity of GSK-3β affects ATRA responsiveness of myeloid cells and how transcriptional activity of RARα and kinase activity of GSK-3β are linked via ATRA-related inhibitory phosphorylation (P) of GSK-3β.