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. 2015 Jul;29(4):263-8.
doi: 10.1016/j.blre.2015.01.002. Epub 2015 Jan 21.

An ATRActive future for differentiation therapy in AML

Daniel E Johnson  1 , Robert L Redner  2
Affiliations

An ATRActive future for differentiation therapy in AML

Daniel E Johnson et al. Blood Rev. 2015 Jul.

Abstract

The success of all-trans retinoic acid (ATRA) therapy in acute promeylocytic leukemia (APL) has spawned numerous attempts to translate the paradigm of differentiation therapy to non-APL acute myelocytic leukemia (AML). However, the results of clinical trials have been overall disappointing. In this review we discuss the mechanism of retinoic acid signaling and the results of major clinical trials that have attempted to incorporate ATRA into AML regimens. We discuss recent evidence that indicate that the retinoic acid signaling pathway may be dysfunctional in AML. Preliminary studies suggest that targeting the pathways that modify retinoic acid receptor activity may reactivate the dormant retinoic acid-signaling pathway. Such strategies may revive the ability of ATRA to induce myeloid differentiation and apoptosis in non-APL AML.

Keywords: AML; ATRA; differentiation therapy.

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Figures

Figure 1
Figure 1
Structure of all-trans retinoic acid.
Figure 2
Figure 2
Schematic demonstrating interaction of RAR with Co-repressor and Co-activator complexes in absence (panel A) and presence (panel B) of ATRA.
Figure 3
Figure 3
Model of epigenetic modulation on activity of RAR: Alteration of histone methylation or acetylation (depicted as red balls) of histones may allow the RAR transcriptional complex to form, but prevents activation of transcription of target genes.
Figure 4
Figure 4
Proposed model of the mechanism underlying synergy between Src Family Kinase inhibition and ATRA. Panel A: activation of SFK tyrosine kinases in AML promotes, either directly or indirectly leads to phosphorylation of RAR, inhibiting the ability of RAR to bind to RXR and/or DNA. Panel B: SKF inhibition blocks the ability of SFKs to promote phosphorylate RAR, allowing RAR to bind normally RXR and DNA targets, and in the presence of ATRA, to regain its ability to function as a transcriptional activator.
See this image and copyright information in PMC

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