title: RALB provides critical survival signals downstream of Ras in acute myeloid leukemia.
abstract: Mutations that activate RAS proto-oncogenes and their effectors are common in acute myeloid leukemia (AML); however, efforts to therapeutically target Ras or its effectors have been unsuccessful, and have been hampered by an incomplete understanding of which effectors are required for AML proliferation and survival. We investigated the role of Ras effector pathways in AML using murine and human AML models. Whereas genetic disruption of NRAS(V12) expression in an NRAS(V12) and Mll-AF9-driven murine AML induced apoptosis of leukemic cells, inhibition of phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) signaling did not reproduce this effect. Conversely, genetic disruption of RALB signaling induced AML cell death and phenocopied the effects of suppressing oncogenic Ras directly - uncovering a novel role for RALB signaling in AML survival. Knockdown of RALB led to decreased phosphorylation of TBK1 and reduced BCL2 expression, providing mechanistic insight into RALB survival signaling in AML. Notably, we found that patient-derived AML blasts have higher levels of RALB-TBK1 signaling compared to normal blood leukocytes, supporting a pathophysiologic role for RALB signaling for AML patients. Overall, our work provides new insight into the specific roles of Ras effector pathways in AML and has identified RALB signaling as a key survival pathway.
authors.affiliation: Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Eckfeldt
authors.affiliation: Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Pomeroy
authors.affiliation: Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Robin D W
authors.initials: RD
authors.lastname: Lee
authors.affiliation: Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Hazen
authors.affiliation: Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Lee
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.|Department of Pediatrics, Division of Hematology and Oncology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Branden S
authors.initials: BS
authors.lastname: Moriarity
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.|Department of Pediatrics, Division of Hematology and Oncology, University of Minnesota, Minneapolis, MN 55455, USA.|Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
mesh_terms: D000818:Animals; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D020725:ral GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C483163:Ralb protein, human; D020725:ral GTP-Binding Proteins; D018631:ras Proteins
keywords: BCL2; RALB; RAS signaling; TBK1; acute myeloid leukemia (AML)