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         headline:Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia
         description: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.
         datePublished:2022-02-21T00:00:00Z
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      headline:Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia
      description: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.
      datePublished:2022-02-21T00:00:00Z
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         Translational research
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         Cancer Research
         Cell Biology
         Pathology
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            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Richard Eric Davis
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Lymphoma & Myeloma Research, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Venkata L. Battula
      url:http://orcid.org/0000-0001-5415-9058
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Yingchang Mi
      affiliation:
            name:Chinese Academy of Medical Sciences & Peking Union Medical College
            address:
               name:Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
               type:PostalAddress
            type:Organization
      name:Jing Wang
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Courtney D. DiNardo
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Michael Andreeff
      url:http://orcid.org/0000-0002-1144-1958
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Jeffery W. Tyner
      affiliation:
            name:Oregon Health & Science University
            address:
               name:Department of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, USA
               type:PostalAddress
            type:Organization
      name:Aaron Schimmer
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Anthony Letai
      url:http://orcid.org/0000-0002-1993-9013
      affiliation:
            name:Dana-Farber Cancer Institute
            address:
               name:Dana-Farber Cancer Institute, Boston, USA
               type:PostalAddress
            type:Organization
      name:Rose Ann Padua
      affiliation:
            name:Université de Paris, Institut de la Recherche Saint-Louis (IRSL), Inserm Unit 1131
            address:
               name:Université de Paris, Institut de la Recherche Saint-Louis (IRSL), Inserm Unit 1131, Paris, France
               type:PostalAddress
            type:Organization
      name:Carlos E. Bueso-Ramos
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Stefano Tiziani
      affiliation:
            name:The University of Texas at Austin
            address:
               name:Department of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, USA
               type:PostalAddress
            type:Organization
      name:Joel Leverson
      affiliation:
            name:AbbVie Inc.
            address:
               name:AbbVie Inc., North Chicago, USA
               type:PostalAddress
            type:Organization
      name:Relja Popovic
      affiliation:
            name:AbbVie Inc.
            address:
               name:AbbVie Inc., North Chicago, USA
               type:PostalAddress
            type:Organization
      name:Marina Konopleva
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:AbbVie Inc., North Chicago, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
      name:Department of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, USA
      name:Department of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, USA
      name:Université de Paris, Institut de la Recherche Saint-Louis (IRSL), Inserm Unit 1131, Paris, France
      name:Dana-Farber Cancer Institute, Boston, USA
      name:Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, USA
      name:Dana-Farber Cancer Institute, Boston, USA
      name:Princess Margaret Cancer Center, Toronto, Canada
      name:High Resolution Electron Microscopy Facility, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:AbbVie Inc., North Chicago, USA
      name:AbbVie Inc., North Chicago, USA
      name:AbbVie Inc., North Chicago, USA
      name:AbbVie Inc., North Chicago, USA
      name:Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Hematology, The First Hospital Affiliated Harbin Medical University, Harbin, China
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Lymphoma & Myeloma Research, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
      name:Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, USA
      name:Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Dana-Farber Cancer Institute, Boston, USA
      name:Université de Paris, Institut de la Recherche Saint-Louis (IRSL), Inserm Unit 1131, Paris, France
      name:Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, USA
      name:AbbVie Inc., North Chicago, USA
      name:AbbVie Inc., North Chicago, USA
      name:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA

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