Abstract
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. 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. 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). 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.
Highlights
The translocation t(15;17) in acute promyelocytic leukemia (APL) was among the first recurrent aberrations detected by chromosome banding analysis in acute myeloid leukemia (AML; ref. 1)
preferentially expressed antigen in melanoma (PRAME) seems to impair differentiation and to increase proliferation likely via blocking retinoic acid receptor (RAR) signaling, which might be reversed by all-trans-retinoic acid (ATRA)
PRAME expression-associated GEP in AML We previously observed that non-APL AML cases, and especially those who are NPM1-mutated, might benefit from a combination of chemotherapy and ATRA [7]
Summary
The translocation t(15;17) in acute promyelocytic leukemia (APL) was among the first recurrent aberrations detected by chromosome banding analysis in acute myeloid leukemia (AML; ref. 1). Molecular insights have grown significantly in non-APL AML based on the advancement of novel technologies allowing comprehensive genomic, transcriptomic, and epigenomic analyses [3,4,5]. NPM1 mutations represent the most frequent genetic alteration found in 45% to 64% of cytogenetically normal acute myeloid leukemia (CN-AML). This entity has been included in the revised World Health Organization classification as novel provisional molecularly defined AML entity. Little is known about the functional role of ATRA in NPM1-mutated AML
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