Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia
| Autor: | Julia E. Maxson, Sarah A. Carratt, Theodore P. Braun, Amy Foley, Rowan Callahan, Lauren Maloney, Brittany M. Smith, Zachary Schonrock, Cody Coblentz |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Neuroblastoma RAS viral oncogene homolog MAPK/ERK pathway Cancer Research Myeloid MAP Kinase Signaling System Pyridones Pyrimidinones Biology medicine.disease_cause Article GTP Phosphohydrolases Mice 03 medical and health sciences 0302 clinical medicine Bone Marrow medicine Animals Humans Protein Kinase Inhibitors Cells Cultured Trametinib Mice Inbred BALB C Juvenile myelomonocytic leukemia MEK inhibitor Membrane Proteins Nuclear Proteins Myeloid leukemia Hematology medicine.disease Mice Inbred C57BL Disease Models Animal Leukemia 030104 developmental biology medicine.anatomical_structure Leukemia Myelomonocytic Juvenile Oncology 030220 oncology & carcinogenesis Mutation Cancer research Carrier Proteins Carcinogenesis Signal Transduction |
| Zdroj: | Leukemia |
| DOI: | 10.1101/2021.02.01.429244 |
| Popis: | Mutations in SET binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging pre-clinical data for the use of trametinib in SETBP1-mutant disease. |
| Databáze: | OpenAIRE |
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