Mouse Model for NRAS-induced Leukemogenesis

Mutations that result in constitutive activation of RAS proteins are common in human hematological malignancies. In addition, functional activation of the RAS pathway can occur in leukemias, either due to mutations in genes that code for proteins upstream of RAS or due to inactivation of negative regulators of RAS. However, despite this prominent association of RAS activation with human leukemias, its precise role in leukemogenesis is not known. Previous studies have met with limited success in developing relevant animal models for leukemogenesis by oncogenic NRAS, the most frequently mutated RAS gene in human leukemias, and have suggested that oncogenic RAS might only act as a secondary event in leukemogenesis. This chapter describes an efficient and relevant murine model for myeloid leukemias initiated by oncogenic NRAS using an improved bone marrow transduction/transplantation system. This model provides a system for further studying the molecular mechanisms in the pathogenesis of myeloid malignancies and for testing targeted therapies.