ArticleSignal transduction and targeted therapy2022
Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia.
Erratum issuedOpen access · goldAbstract read
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Article in Signal transduction and targeted therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 139 papers.
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139citing papers in PubMed
26.9field-weighted citation impact, top 1% of its field
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Who cites it
139 citing papers in PubMed, 173 citations in OpenAlex.
- Results of a phase 1 trial testing ruxolitinib plus venetoclax in patients with relapsed/refractory acute myeloid leukemia.Blood neoplasia · 2026Trial
- Reduced dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia following intensive or low-intensity induction: a single-centre, single-arm, phase 2 trial.The Lancet. Haematology · 2024Trial
- Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study.The Lancet. Haematology · 2024Trial
- Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.Haematologica · 2026Article
- Melatonin potentiates the antineoplastic effects of venetoclax in acute myeloid leukemia cells.Hematology, transfusion and cell therapy · 2026Article
- Dynamic genetic and nongenetic RAS-pathway activation drives resistance to FLT3 and BCL2 inhibitor therapy.Blood · 2026Article
- Wired to Survive: How AML Cytogenetics Shape Apoptotic Dependence and Venetoclax Resistance.Genes · 2026Review
- Brusatol Triggers Cell Cycle Arrest and Apoptosis, Disrupts Sterol Biosynthesis, and Enhances the Anti-Leukemic Activity of Venetoclax in AML Cells.Cell biochemistry and biophysics · 2026Article
- CD84 expression stratifies venetoclax response and reveals a targetable vulnerability in resistant acute myeloid leukemia.Experimental hematology & oncology · 2026Article
- Bone marrow stromal cells promote chemoresistance in acute myeloid leukaemia through P2RX7-mediated antioxidant defence.Experimental & molecular medicine · 2026Article
- Venetoclax for elderly patients with acute myeloid leukaemia unfit for intensive chemotherapy: Prospects, resistance mechanisms and management strategies.Clinical and translational medicine · 2026Review
- m6A and NuRD complexes regulate monocytic differentiation and resistance to BCL2/BCL2L1 inhibitors in acute myeloid leukemia.Haematologica · 2026Article
- Article
- Translocation t(11;14) and BCL2-inhibition in multiple myeloma.Haematologica · 2026Review
- TRIM24 stabilizes the p110 CUX1 oncoprotein via USP10 to promote chemoresistance in acute myeloid leukemia.Journal of translational medicine · 2026Article
- Clinical implications of RAS mutations in AML: prognostic significance is based upon the involved gene and mutation complexity.Blood advances · 2026Article
- Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.Cell death & disease · 2026Article
- Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting.Oncogenesis · 2026Review
- Synergistic targeting of eIF4A-mediated translation initiation and apoptosis in acute myeloid leukemia.Blood neoplasia · 2026Article
- A Deep Learning Model for IMMP-Based Residual Disease Monitoring in AML with Monocytic Differentiation.Diagnostics (Basel, Switzerland) · 2026Article
79 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
41 authors at 8 institutions in 4 countries.
Qi ZhangDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0002-7918-8952
Bridget Riley-GillisAbbVie Inc., North Chicago, IL, USA.
Lina HanDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yannan JiaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Alessia LodiDepartment of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA.
Haijiao ZhangDepartment of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
Saravanan GanesanUniversité de Paris, Institut de la Recherche Saint-Louis (IRSL), Inserm Unit 1131, Paris, France.
Rongqing PanDana-Farber Cancer Institute, Boston, MA, USA.
Sergej N KonoplevDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Shannon R SweeneyDepartment of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA.
Jeremy A RyanDana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-3327-1283
Yulia JitkovaPrincess Margaret Cancer Center, Toronto, ON, Canada.
Kenneth DunnerHigh Resolution Electron Microscopy Facility, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Shaun E GrosskurthAbbVie Inc., North Chicago, IL, USA.
Priyanka VijayAbbVie Inc., North Chicago, IL, USA.ORCID http://orcid.org/0000-0002-6032-9081
Sujana GhoshAbbVie Inc., North Chicago, IL, USA.
Charles LuAbbVie Inc., North Chicago, IL, USA.
Wencai MaDepartment of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Stephen KurtzDepartment of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
Vivian R RuvoloDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Helen MaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Connie C WengDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cassandra L RamageDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Natalia BaranDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0003-0618-4798
Ce ShiDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Tianyu CaiDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Richard Eric DavisDepartment of Lymphoma & Myeloma Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Venkata L BattulaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0001-5415-9058
Yingchang MiInstitute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Jing WangDepartment of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Courtney D DiNardoDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Michael AndreeffDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0002-1144-1958
Jeffery W TynerDepartment of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
Aaron SchimmerDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Anthony LetaiDana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-1993-9013
Rose Ann PaduaUniversité de Paris, Institut de la Recherche Saint-Louis (IRSL), Inserm Unit 1131, Paris, France.
Carlos E Bueso-RamosDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Stefano TizianiDepartment of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA.
Joel LeversonAbbVie Inc., North Chicago, IL, USA.
Relja PopovicAbbVie Inc., North Chicago, IL, USA.
Marina KonoplevaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mkonople@mdanderson.org.
The University of Texas MD Anderson Cancer Center · USAbbVie (United States) · USDana-Farber Cancer Institute · USOregon Health & Science University · USThe University of Texas at Austin · USInserm · FRChinese Academy of Medical Sciences & Peking Union Medical College · CNPrincess Margaret Cancer Centre · CA
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Fabien Delerue · 1985 to 2026
$290.8MTYROSINE KINASE ONCOGENESIS IN MYELOID LEUKEMIAP01CA066996 · NCI · DANA-FARBER CANCER INSTITUTE · PI SCOTT A ARMSTRONG · 1996 to 2026
$52.5MUniversity of Texas M.D. Anderson Cancer SPORE-LeukemiaP50CA100632 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI SHPALL, ELIZABETH J · 2003 to 2023
$43.7MTumor Intrinsic and Microenvironmental Mechanisms Driving Drug Combination Efficacy and Resistance in AMLU54CA224019 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI BRIAN J DRUKER, Shannon K. McWeeney · 2017 to 2026
$13.9MReading mitochondrial apoptotic signaling to identify active cancer therapeuticsR35CA242427 · NCI · DANA-FARBER CANCER INST · PI LETAI, ANTHONY G · 2019 to 2025
$7.0MMechanisms of venetoclax combination activity in acute myeloid leukemiaR01CA262758 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI Stephen E Kurtz, Jeffrey Wallace Tyner · 2021 to 2026
$2.1MTargeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimenR01CA235622 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KONOPLEVA, MARINA Y, SPENCER, DAVID H · 2019 to 2024
$1.8MNCI NIH HHS P01 CA066996NCI NIH HHS P30 CA016672NCI NIH HHS P50 CA100632NCI NIH HHS R01 CA235622NCI NIH HHS R01 CA262758NCI NIH HHS R35 CA242427NCI NIH HHS U54 CA224019
Abstract
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.
Indexed as
Bridged Bicyclo Compounds, HeterocyclicLeukemia, Myeloid, AcuteMAP Kinase Signaling SystemMyeloid Cell Leukemia Sequence 1 ProteinProto-Oncogene Proteins c-bcl-2ras ProteinsSulfonamidesCell Line, TumorDrug Resistance, NeoplasmHumansBCL2 protein, humanBridged Bicyclo Compounds, HeterocyclicMCL1 protein, humanMyeloid Cell Leukemia Sequence 1 ProteinProto-Oncogene Proteins c-bcl-2ras ProteinsSulfonamidesvenetoclax
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