Qi Zhang ORCID: orcid.org/0000-0002-7918-8952,Bridget Riley-Gillis,Lina Han,Yannan Jia,Alessia Lodi,Haijiao Zhang,Saravanan Ganesan,Rongqing Pan,Sergej N. Konoplev,Shannon R. Sweeney,Jeremy A. Ryan ORCID: orcid.org/0000-0002-3327-1283,Yulia Jitkova,Kenneth Dunner Jr,Shaun E. Grosskurth,Priyanka Vijay ORCID: orcid.org/0000-0002-6032-9081,Sujana Ghosh,Charles Lu,Wencai Ma,Stephen Kurtz,Vivian R. Ruvolo,Helen Ma,Connie C. Weng,Cassandra L. Ramage,Natalia Baran ORCID: orcid.org/0000-0003-0618-4798,Ce Shi,Tianyu Cai,Richard Eric Davis,Venkata L. Battula ORCID: orcid.org/0000-0001-5415-9058,Yingchang Mi,Jing Wang,Courtney D. DiNardo,Michael Andreeff ORCID: orcid.org/0000-0002-1144-1958,Jeffery W. Tyner,Aaron Schimmer,Anthony Letai ORCID: orcid.org/0000-0002-1993-9013,Rose Ann Padua,Carlos E. Bueso-Ramos,Stefano Tiziani,Joel Leverson,Relja Popovic &…Marina Konopleva

Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2–selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.

https://doi.org/10.1038/s41392-021-00870-3

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