The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo ... View Full Text


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Article Info

DATE

2022-08-22

AUTHORS

Ruth Meier, Gabriele Greve, Dennis Zimmer, Helena Bresser, Bettina Berberich, Ralitsa Langova, Julia Stomper, Anne Rubarth, Lars Feuerbach, Daniel B. Lipka, Joschka Hey, Björn Grüning, Benedikt Brors, Justus Duyster, Christoph Plass, Heiko Becker, Michael Lübbert

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. More... »

PAGES

122

References to SciGraph publications

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    http://scigraph.springernature.com/pub.10.1038/s41408-022-00715-4

    DOI

    http://dx.doi.org/10.1038/s41408-022-00715-4

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1150396824

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/35995769


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    348 Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
    349 rdf:type schema:Organization
    350 grid-institutes:grid.7700.0 schema:alternateName Faculty of Bioscience, University of Heidelberg, Heidelberg, Germany
    351 schema:name Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany
    352 Faculty of Bioscience, University of Heidelberg, Heidelberg, Germany
    353 rdf:type schema:Organization
     




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