The RAS family proteins (NRAS, HRAS and KRAS 4B/4A) are small GTPases that play a key role in transducing signals that regulate cell proliferation, survival and differentiation. The RAS proteins share a high degree of sequence identity, 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.

RAS mutations are associated with nearly 30% of all human cancers, including hematological malignancies. Mutations that result in constitutive activation of the RAS proteins are found in nearly 20-30% of acute myeloid leukemia (AML) and 50-70% of chronic myelomonocytic leukemia (CMML). In addition, functional activation of the RAS pathway can result from mutations in genes that code for proteins upstream of RAS or due to inactivation of negative regulators of RAS. However, the precise role of RAS activation in the pathogenesis of myeloid leukemias is not known. Previous studies in animal models have shown that oncogenic RAS is unable to induce myeloid malignancies effectively and it was suggested that oncogenic RAS might only act as a secondary event in leukemogenesis. In this study, we examined the leukemogenecity of NRAS using an improved mouse bone marrow transduction and transplantation model. We found that oncogenic NRAS rapidly and efficiently induced CMML- or AML-like disease in mice, indicating that mutated NRAS can function as an initiating oncogene in the induction of myeloid malignancies.

Interestingly, different RAS oncogenes are preferentially associated with different types of human cancer. In myeloid malignancies, NRAS mutations are frequent (in approximately 70% of cases), followed by KRAS mutations, while HRAS mutations are rare. To gain insights into the mechanisms underlying the different frequencies of RAS isoforms mutated in myeloid leukemia, we compared the ability of the three oncogenic RAS proteins to induce leukemias using the same animal model. We found that in the same model system, although NRAS can induce an AML or a CMML-like disease, mutated 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. 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.