The Deacetylases HDAC1 and HDAC2 Safeguard BCR-ABL-positive Cells from Replication Stress-Induced Apoptosis via the Nuclear to Mitochondrial p73-NOXA Axis

Abstract Histone deacetylases (HDACs) are key epigenetic regulators that are frequently dysregulated in cancer cells. Context-specific dependencies of tumor cell survival on HDACs and the mechanisms through which HDACs determine cell stress responses by specific oncogenic pathways remain to be understood. Here we unravel how the class I deacetylases HDAC1 and HDAC2 control the fate of chronic myeloid leukemia (CML) cells undergoing DNA replication stress. Compared to normal myeloid cells (n=690), CML cells overexpress HDAC1 and HDAC2 (n=234-274). We reveal that HDAC1 and HDAC2 protect cultured and primary CML cells with the hyperactive BCR-ABL tyrosine kinase from programmed cell death through apoptosis upon DNA replication stress. Using transcriptomics and genetically defined knockdown and knockout model systems, we demonstrate that these effects depend on the transcription factor p73 and its pro-apoptotic target gene NOXA. Upon DNA replication stress, p73 binds to the NOXA promoter but only upon additional inactivation of HDAC1/HDAC2 the NOXA gene becomes transcribed. BCR-ABL translocate to the nucleus to catalyze p73 phosphorylation at tyrosine-99 for the induction of p73 and mitochondrial NOXA. Thus, the BCR-ABL oncogene creates a selective vulnerability to HDAC1/HDAC2 inhibitors, driving a cytotoxic shift in replication stress responses towards apoptosis. These data highlight HDAC1/HDAC2 as potential therapeutic targets in CML. Competing Interest Statement Dear Editors, I declare the patents The use of molecular markers for the preclinical and clinical profiling of inhibitors of enzymes having histone deacetylase activity, WO/2004/027418, Novel HDAC6 inhibitors and their uses, WO2016020369A1, and Synthesis, pharmacology and use of new and selective FMS-like tyrosine kinase 3 (FLT3) inhibitors, WO2019/034538, and advisory consultant activity for BASF, Ludwigshafen, Germany. The substances that are covered in these patents are not those that are shown in the submitted manuscript. Thus, there are no direct competing interests. All other authors declare that they have no conflict of interest. Sincerely, Prof. Dr. Oliver H. Kramer