@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 Gruning, Bjorn 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},
  volume =	 {12},
  number =	 {8},
  pages =	 {122},
  user =	 {backofen},
  pmid =	 {35995769},
  doi = 	 {10.1038/s41408-022-00715-4},
  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.}
}