Nf1 deficiency cooperates with oncogenic K-RAS to induce acute myeloid leukemia in mice.
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.
Cutts
Briony A
BA
Wallenberg Laboratory, Institute of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
Sjogren
Anna-Karin M
AK
Andersson
Karin M E
KM
Wahlstrom
Annika M
AM
Karlsson
Christin
C
Swolin
Birgitta
B
Bergo
Martin O
MO
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
D006454:Hemoglobins; D025542:Neurofibromin 1; D012333:RNA, Messenger; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)