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Despite promising response rates, many patients do not achieve sustained remission or are upfront refractory. Identification of resistance mechanisms and additional therapeutic targets represent unmet clinical needs. By using a genome-wide CRISPR\/Cas9 library screen targeting 18,053 protein- coding genes in a human AML cell line, various genes conferring resistance to combined venetoclax\/azacitidine treatment were identified. The ribosomal protein S6 kinase A1 (RPS6KA1) was among the most significantly depleted sgRNA-genes in venetoclax\/azacitidine- treated AML cells. Addition of the RPS6KA1 inhibitor BI-D1870 to venetoclax\/azacitidine decreased proliferation and colony forming potential compared to venetoclax\/azacitidine alone. Furthermore, BI-D1870 was able to completely restore the sensitivity of OCI-AML2 cells with acquired resistance to venetoclax\/azacitidine. Analysis of cell surface markers revealed that RPS6KA1 inhibition efficiently targeted monocytic blast subclones as a potential source of relapse upon venetoclax\/azacitidine treatment. Taken together, our results suggest RPS6KA1 as mediator of resistance towards venetoclax\/azacitidine and additional RPS6KA1 inhibition as strategy to prevent or overcome resistance.<\/jats:p>","DOI":"10.1038\/s41375-023-01951-8","type":"journal-article","created":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T17:01:35Z","timestamp":1688662895000},"page":"1611-1625","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The ribosomal protein S6 kinase alpha-1 (RPS6KA1) induces resistance to venetoclax\/azacitidine in acute myeloid leukemia"],"prefix":"10.1038","volume":"37","author":[{"given":"Katharina","family":"Weidenauer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Rohde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius","family":"Pauli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7524-4080","authenticated-orcid":false,"given":"Maximilian F.","family":"Blank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Heid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Waclawiczek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3123-9975","authenticated-orcid":false,"given":"Anika","family":"Corbacioglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"G\u00f6llner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2633-1767","authenticated-orcid":false,"given":"Michelle","family":"Lotze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3661-6512","authenticated-orcid":false,"given":"Lisa","family":"Vierbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Renders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7549-9326","authenticated-orcid":false,"given":"Jeroen","family":"Krijgsveld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Raffel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Sauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6212-3466","authenticated-orcid":false,"given":"Andreas","family":"Trumpp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9716-5909","authenticated-orcid":false,"given":"Caroline","family":"Pabst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7166-5232","authenticated-orcid":false,"given":"Carsten","family":"M\u00fcller-Tidow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9899-1022","authenticated-orcid":false,"given":"Maike","family":"Janssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,6]]},"reference":[{"key":"1951_CR1","first-page":"1","volume":"6","author":"AM Almeida","year":"2016","unstructured":"Almeida AM, Ramos F. 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