Journal
BLOOD
Volume 114, Issue 17, Pages 3629-3632Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-02-205146
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Funding
- European Research Council
- Swedish Medical Research Council
- Swedish Cancer Society
- Swedish Children's Cancer Fund
- Vastra Gotalandsregionen
- European Hematology Association Jose Carreras Young Investigator Fellowship Program
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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. (Blood. 2009;114:3629-3632)
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