@article{Meier_Greve_Zimmer-The_antil_activ-2022,
author = {Meier, Ruth and Greve, Gabriele and Zimmer, Dennis and 
          Bresser, Helena and Berberich, Bettina and Langova, Ralitsa 
          and Stomper, Julia and Rubarth, Anne and Feuerbach, Lars and 
          Lipka, Daniel B. and Hey, Joschka and Grüning, Björn and 
          Brors, Benedikt and Duyster, Justus and Plass, Christoph and 
          Becker, Heiko and Lubbert, Michael},
title = {The antileukemic activity of decitabine upon 
         {PML}/{RARA}-negative {AML} blasts is supported by all-trans 
         retinoic acid: in vitro and in vivo evidence for cooperation},
journal = {Blood Cancer J},
year = {2022},
doi = {10.1038/s41408-022-00715-4},
volume = {12},
user = {backofen},
pmid = {35995769},
pages = {122},
number = {8},
issn = {2044-5385},
abstract = {The prognosis of AML patients with adverse genetics, such 
            as a complex, monosomal karyotype and TP53 lesions, is still 
            dismal even with standard chemotherapy. DNA-hypomethylating 
            agent monotherapy induces an encouraging response rate in 
            these patients. When combined with decitabine (DAC), 
            all-trans retinoic acid (ATRA) resulted in an improved 
            response rate and longer overall survival in a randomized 
            phase II trial (DECIDER; NCT00867672). The molecular 
            mechanisms governing this in vivo synergism are unclear. We 
            now demonstrate cooperative antileukemic effects of DAC and 
            ATRA on AML cell lines U937 and MOLM-13. By RNA-sequencing, 
            derepression of >1200 commonly regulated transcripts 
            following the dual treatment was observed. Overall chromatin 
            accessibility (interrogated by ATAC-seq) and, in particular, 
            at motifs of retinoic acid response elements were affected 
            by both single-agent DAC and ATRA, and enhanced by the dual 
            treatment. Cooperativity regarding transcriptional induction 
            and chromatin remodeling was demonstrated by interrogating 
            the HIC1, CYP26A1, GBP4, and LYZ genes, in vivo gene 
            derepression by expression studies on peripheral blood 
            blasts from AML patients receiving DAC + ATRA. The two drugs 
            also cooperated in derepression of transposable elements, 
            more effectively in U937 (mutated TP53) than MOLM-13 (intact 
            TP53), resulting in a "viral mimicry" response. In 
            conclusion, we demonstrate that in vitro and in vivo, the 
            antileukemic and gene-derepressive epigenetic activity of 
            DAC is enhanced by ATRA.}
}