title: Oncogenic NRAS Primes Primary Acute Myeloid Leukemia Cells for Differentiation.
abstract: RAS mutations are frequently found among acute myeloid leukemia patients (AML), generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We have previously shown that treatment of AML patients with high-dose cytarabine is preferentially beneficial for those harboring oncogenic RAS. On the basis of a murine AML cell culture model, we ascribed this effect to a RAS-driven, p53-dependent induction of differentiation. Hence, in this study we sought to confirm the correlation between RAS status and differentiation of primary blasts obtained from AML patients. The gene expression signature of AML blasts with oncogenic NRAS indeed corresponded to a more mature profile compared to blasts with wildtype RAS, as demonstrated by gene set enrichment analysis (GSEA) and real-time PCR analysis of myeloid ecotropic viral integration site 1 homolog (MEIS1) in a unique cohort of AML patients. In addition, in vitro cell culture experiments with established cell lines and a second set of primary AML cells showed that oncogenic NRAS mutations predisposed cells to cytarabine (AraC) driven differentiation. Taken together, our findings show that AML with inv(16) and NRAS mutation have a differentiation gene signature, supporting the notion that NRAS mutation may predispose leukemic cells to AraC induced differentiation. We therefore suggest that promotion of differentiation pathways by specific genetic alterations could explain the superior treatment outcome after therapy in some AML patient subgroups. Whether a differentiation gene expression status may generally predict for a superior treatment outcome in AML needs to be addressed in future studies.
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Clinic Giessen and Marburg, Marburg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Clinic Giessen and Marburg, Marburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Teichler
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Clinic Giessen and Marburg, Marburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Millahn
authors.affiliation: Molecular Oncology, Philipps University of Marburg, Marburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
authors.affiliation: Molecular Oncology, Philipps University of Marburg, Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Krause
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Clinic Giessen and Marburg, Marburg, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Stabla
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Clinic Giessen and Marburg, Marburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Ross
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Clinic Giessen and Marburg, Marburg, Germany.
authors.forename: Minh
authors.initials: M
authors.lastname: Huynh
authors.affiliation: Medical Clinic I, University Clinic of Technical University Dresden, Dresden, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illmer
authors.affiliation: Molecular Oncology, Philipps University of Marburg, Marburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Mernberger
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Clinic Giessen and Marburg, Marburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Barckhausen
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Clinic Giessen and Marburg, Marburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubauer
mesh_terms: D000368:Aged; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015331:Cohort Studies; D003561:Cytarabine / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; D008565:Membrane Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C471254:inv(16) fusion protein, human; D003561:Cytarabine; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D018631:ras Proteins