Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis

This project was supported by the FEDER/Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación through the grant PIE16/00011 RESPONSE (to M.B.), the European Research Council ERC-StG-336860 (to J.Z.), the grant Juan de la Cierva- Formación FJCI-2014-22983 (to J.D.), the grant Sara Borrell CD17/00084 (to J.D.), the Marie Skłodowska Curie Training network "ChroMe" H2020-MSCA-ITN-2015-675610 (to M.M.), the FPI predoctoral fellowship BES-2016-077251 (to M.M.L.P.), the SFB 1243 DFG (to K.S.G.), the Austrian Science Fund SFB-F4710 (to J.Z.) and the Deutsche José Carreras Leukämie Stiftung DJCLS 14R/2018 (to K.G. and M.B.). Research in the Buschbeck lab is further supported by the following grants: MINECO grant RTI2018-094005-B-I00 (to M.B.), the Marie Skłodowska Curie Training network 'INTERCEPT-MDS' H2020-MSCA-ITN-2015-953407 (to M.B. and K.S.G.); AGAUR 2017-SGR-305 (to M.B.) and Fundació La Marató de TV3 257/C/2019 (to M.B.). Research at IMP is supported by Boehringer Ingelheim, the Austrian Research Promotion Agency (Headquarter grant FFG-852936) and the Austrian Academy of Sciences. Research at the IJC is generously supported by the 'La Caixa' Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Programme/Generalitat de Catalunya. A.G. received funds by "Agencia Estatal de Investigación" (AEI) through the Plan Nacional "Excelencia" grant number SAF2017-84301-P, by the "Associación Española Contra el Cancer" (AECC) grant number LABAE20040GENT and by the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR01743. Proteomic analyses were performed in the IJC Proteomic Unit, which are part of Proteored PRB3 and are supported by grant PT17/0019 from the PE I + D + i 2013-2016, funded by ISCIII and ERDF. We thank Kaoru Tohyama for providing MDS-L cells, members of the Buschbeck lab, the RESPONSE network (PIE16/00011), Blanca Xicoy and Francesc Solé for valuable discussions. We thank the IJC Biobanking unit for sample preparation and storage, Bernat Cucurull from the IJC Proteomics unit for the ClickIT sample preparation, Marco Fernandez for advice and training in flow cytometry and all other staff of IJC and IGTP core facilities for excellent support. 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