%0 Journal Article %1 Diesch2021 %A Diesch, Jeannine %A Le Pannérer, Marguerite-Marie %A Winkler, René %A Casquero, Raquel %A Muhar, Matthias %A van der Garde, Mark %A Maher, Michael %A Herráez, Carolina Martínez %A Bech-Serra, Joan J. %A Fellner, Michaela %A Rathert, Philipp %A Brooks, Nigel %A Zamora, Lurdes %A Gentilella, Antonio %A de la Torre, Carolina %A Zuber, Johannes %A Götze, Katharina S. %A Buschbeck, Marcus %D 2021 %J Nature Communications %K ibtb-bc myown philipprathert %N 1 %P 6060 %R 10.1038/s41467-021-26258-z %T Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis %U https://doi.org/10.1038/s41467-021-26258-z %V 12 %X The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis.

@article{Diesch2021, abstract = {The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis.}, added-at = {2022-02-24T15:16:23.000+0100}, author = {Diesch, Jeannine and Le Pann{\'e}rer, Marguerite-Marie and Winkler, Ren{\'e} and Casquero, Raquel and Muhar, Matthias and van der Garde, Mark and Maher, Michael and Herr{\'a}ez, Carolina Mart{\'i}nez and Bech-Serra, Joan J. and Fellner, Michaela and Rathert, Philipp and Brooks, Nigel and Zamora, Lurdes and Gentilella, Antonio and de la Torre, Carolina and Zuber, Johannes and G{\"o}tze, Katharina S. and Buschbeck, Marcus}, biburl = {https://puma.ub.uni-stuttgart.de/bibtex/27977cf0153c466e3a4a82009a184921f/philipprathert}, day = 18, doi = {10.1038/s41467-021-26258-z}, interhash = {8af3acc4e8d0cd2642c1a2d1439b21e2}, intrahash = {7977cf0153c466e3a4a82009a184921f}, issn = {2041-1723}, journal = {Nature Communications}, keywords = {ibtb-bc myown philipprathert}, month = oct, number = 1, pages = 6060, timestamp = {2022-02-24T14:16:23.000+0100}, title = {Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis}, url = {https://doi.org/10.1038/s41467-021-26258-z}, volume = 12, year = 2021 }