Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia

Qi Zhang, Bridget Riley-Gillis, Lina Han, Yanan Jia, Alessia Lodi, Haijiao Zhang, Saravanan Ganesan, Rongqing Pan, Sergej N. Konoplev, Shannon R. Sweeney, Jeremy A. Ryan, Yulia Jitkova, Kenneth Dunner, Shaun E. Grosskurth, Priyanka Vijay, Sujana Ghosh, Charles Lu, Wencai Ma, Stephen Kurtz, Vivian R. RuvoloHelen Ma, Connie C. Weng, Cassandra L. Ramage, Natalia Baran, Ce Shi, Tianyu Cai, Richard Eric Davis, Venkata L. Battula, Yingchang Mi, Jing Wang, Courtney D. DiNardo, Michael Andreeff, Jeffery W. Tyner, Aaron Schimmer, Anthony Letai, Rose Ann Padua, Carlos E. Bueso-Ramos, Stefano Tiziani, Joel Leverson, Relja Popovic, Marina Konopleva

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish (US)
Article number51
JournalSignal Transduction and Targeted Therapy
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Genetics
  • Cancer Research


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