Oncogenic NRAS, KRAS, and HRAS Induce Distinct Hematological Diseases in Mice.

RAS family proteins (NRAS, HRAS and KRAS 4B/4A) are small GTPases that play a central role in transducing signals that regulate cell proliferation, survival and differentiation. The RAS proteins interact with a common set of activators and effectors and, therefore, share many biochemical and biological functions. However, the RAS proteins associate with different microdomains of the plasma membrane as well as other internal cell membranes and are capable of generating distinct signal outputs. Mutations that result in constitutive activation of RAS proteins are associated with approximately 30% of all human cancers, including 20–30% acute myeloid leukemia (AML) and 50–70% chronic myelomonocytic leukemia (CMML). Different RAS oncogenes are preferentially associated with different types of human cancer. In myeloid malignancies, NRAS mutations occur (in approximately 70% of cases), more frequently than KRAS mutations, while HRAS mutations are rare. The mechanism underlying the different frequencies of RAS isoforms mutated in myeloid leukemia is not known. One possibility is that oncogenic RAS proteins have different leukemogenic potentials. To test this possibility, we compared the ability of the three oncogenic RAS proteins to induce leukemias using the same animal model. We have shown previously that oncogenic NRAS rapidly and efficiently induces CMML- or AML-like disease in an improved mouse bone marrow transduction and transplantation model. We found here that in the same model system, oncogenic KRAS invariably induces a CMML-like disease that is similar to what has been shown in a mouse conditional knock in model for oncogenic KRAS. Surprisingly, all mice receiving oncogenic HRAS infected bone marrow cells develop an AML-like disease. The HRAS mice have the shortest disease latency, followed by NRAS and then KRAS. HRAS induced disease also appears to be more aggressive than N or KRAS and is usually accompanied by massive pulmonary infiltration and hemorrhages. These studies demonstrate that all three RAS oncogenes have the potential to induce myeloid leukemias, yet have distinct leukemogenic potentials. The underlying mechanism of the discrepancy between the frequency of HRAS mutation in human myeloid leukemia and its leukemogenic potential in mice is not clear, but the models established here provide a system for further studying the molecular mechanisms in the pathogenesis of myeloid malignancies and for testing targeted therapies.