title: Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia.
abstract: Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.
authors.affiliation: Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Pomeroy
authors.affiliation: Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Lee
authors.affiliation: Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
authors.forename: R D W
authors.initials: RDW
authors.lastname: Lee
authors.affiliation: Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Schirm
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Temiz
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.|Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Gruber
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Diaz-Flores
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Department of Pediatrics, Division of Hematology and Oncology, Minneapolis, MN, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Moriarity
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Shannon
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Department of Pediatrics, Division of Hematology and Oncology, Minneapolis, MN, USA.|Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Eckfeldt
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009857:Oncogenes; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C483163:Ralb protein, human; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D020559:Monomeric GTP-Binding Proteins; D020725:ral GTP-Binding Proteins