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PRAME induced inhibition of retinoic acid receptor signaling-mediated differentiation - a possible target for ATRA response in AML without t(15;17)


ABSTRACT: 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, PRAME (preferentially expressed antigen in melanoma) 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 by profiling gene expression in K562 cell lines. 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 demonstrate that retinoic acid-regulated cell proliferation and differentiation are impacted by PRAME expression. Conclusions: PRAME seems to impair differentiation and to increase proliferation likely via blocking RAR-signaling, which might be reversed by ATRA. For the cell line model GEP was performed using Affymetrix Human Genome U133plus2.0 Array technology according to the manufacturerM-bM-^@M-^Ys recommendations as previously reported. siRNA and scrRNA treated as well as ATRA treated K562 cells stemming from independent experiments were profiled. Using the BRB Array Tools software package fluorescence ratios were normalized by applying the RMA algorithm and supervised ClassComparison PathwayClassComparison analyses were performed.

ORGANISM(S): Homo sapiens

SUBMITTER: Lars Bullinger 

PROVIDER: E-GEOD-43258 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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PRAME-induced inhibition of retinoic acid receptor signaling-mediated differentiation--a possible target for ATRA response in AML without t(15;17).

Bullinger Lars L   Schlenk Richard F RF   Götz Marlies M   Botzenhardt Ursula U   Hofmann Susanne S   Russ Annika C AC   Babiak Anna A   Zhang Lu L   Schneider Vanessa V   Döhner Konstanze K   Schmitt Michael M   Döhner Hartmut H   Greiner Jochen J  

Clinical cancer research : an official journal of the American Association for Cancer Research 20130226 9


<h4>Purpose</h4>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.<h4>Experimental design</h4>Thus, we further investigated ATRA response mechanisms, especially the impact of PRAME expression on ATRA responsivenes  ...[more]

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