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Analysis of Retinoic Acid-induced Neural Differentiation of Mouse Embryonic Stem Cells in Two and Three-dimensional Embryoid Bodies
Published on: April 22, 2017
PRAME-induced inhibition of retinoic acid receptor signaling-mediated differentiation--a possible target for ATRA
Lars Bullinger1, Richard F Schlenk, Marlies Götz
1Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Purpose:
In acute myeloid leukemia (AML) without retinoic acid receptor (RAR) rearrangement, the effect of all-trans-retinoic acid (ATRA) is still poorly understood despite an association of NPM1 mutation and ATRA response. Recently, preferentially expressed antigen in melanoma (PRAME) has been shown to be a dominant repressor of RAR signaling.
Experimental Design:
Thus, we further investigated ATRA response mechanisms, especially the impact of PRAME expression on ATRA responsiveness. We profiled gene expression in diagnostic samples derived from our AML HD98B trial, in which ATRA was administered in addition to intensive chemotherapy.
Results:
Our data revealed a PRAME expression-associated gene pattern to be significantly enriched for genes involved in the retinoic acid metabolic process. In leukemia cell line models, we could show that retinoic acid-regulated cell proliferation and differentiation are impacted by PRAME expression. In patients with primary AML, repressor activity of high-PRAME levels might be overcome by the addition of ATRA as indicated by better outcome in 2 independent studies (P = 0.029).
Conclusions:
PRAME seems to impair differentiation and to increase proliferation likely via blocking RAR signaling, which might be reversed by ATRA. PRAME therefore represents a promising target for both ATRA treatment and possibly future immunotherapeutic approaches in AML.
Insights
Preferentially expressed antigen in melanoma (PRAME) represses retinoic acid signaling in acute myeloid leukemia (AML). ATRA treatment may overcome PRAME
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- Acute myeloid leukemia (AML) treatment efficacy is variable.
- All-trans-retinoic acid (ATRA) response is poorly understood in AML without RAR rearrangement.
- NPM1 mutation is associated with ATRA response.
Purpose of the Study:
- Investigate the impact of PRAME expression on ATRA responsiveness in AML.
- Elucidate ATRA response mechanisms in AML.
- Determine PRAME's role in RAR signaling.
Main Methods:
- Gene expression profiling of diagnostic AML samples from the HD98B trial.
- Analysis of ATRA-treated intensive chemotherapy regimens.
- Leukemia cell line models to assess PRAME's impact on retinoic acid-regulated processes.
Main Results:
- PRAME expression correlated with genes in the retinoic acid metabolic pathway.
- PRAME expression significantly impacted retinoic acid-regulated cell proliferation and differentiation in vitro.
- High PRAME levels in AML patients were associated with better outcomes when treated with ATRA (P = 0.029).
Conclusions:
- PRAME may inhibit AML cell differentiation and promote proliferation by blocking RAR signaling.
- ATRA treatment could potentially reverse PRAME-mediated effects.
- PRAME is a potential therapeutic target for ATRA and immunotherapy in AML.
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