title: Nf1 deficiency cooperates with oncogenic K-RAS to induce acute myeloid leukemia in mice.
abstract: Hyperactive RAS signaling is caused by mutations in RAS genes or a deficiency of the neurofibromatosis gene (NF1) and is common in myeloid malignancies. In mice, expression of oncogenic K-RAS or inactivation of Nf1 in hematopoietic cells results in myeloproliferative disorders (MPDs) that do not progress to acute myeloid leukemia (AML). Because NF1 is a RAS-GTPase-activating protein it has been proposed that NF1 deficiency is functionally equivalent to an oncogenic RAS. It is not clear, however, whether Nf1 deficiency would be redundant in K-RAS-induced MPD development or whether the 2 mutations would cooperate in leukemogenesis. Here, we show that the simultaneous inactivation of Nf1 and expression of K-RAS(G12D) in mouse hematopoietic cells results in AML that was fatal in primary mice within 4 weeks and transplantable to sublethally irradiated secondary recipients. The data point to a strong cooperation between Nf1 deficiency and oncogenic K-RAS.
authors.affiliation: Wallenberg Laboratory, Institute of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Briony A
authors.initials: BA
authors.lastname: Cutts
authors.forename: Anna-Karin M
authors.initials: AK
authors.lastname: Sjogren
authors.forename: Karin M E
authors.initials: KM
authors.lastname: Andersson
authors.forename: Annika M
authors.initials: AM
authors.lastname: Wahlstrom
authors.forename: Christin
authors.initials: C
authors.lastname: Karlsson
authors.forename: Birgitta
authors.initials: B
authors.lastname: Swolin
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003043:Cocarcinogenesis; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D016514:Genes, Neurofibromatosis 1 / Q000502:physiology*; D006454:Hemoglobins / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D025542:Neurofibromin 1 / Q000172:deficiency*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D006454:Hemoglobins; D025542:Neurofibromin 1; D012333:RNA, Messenger; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)