Mechanistic and Preclinical Insights from Mouse Models of Hematologic Cancer Characterized by Hyperactive Ras

RAS genes are mutated in 5%-40% of a spectrum of myeloid and lymphoid cancers with NRAS affected 2-3 times more often than KRAS Genomic analysis indicates that RAS mutations generally occur as secondary events in leukemogenesis, but are integral to the disease phenotype. The tractable nature of the hematopoietic system has facilitated generating accurate mouse models of hematologic malignancies characterized by hyperactive Ras signaling. These strains provide robust platforms for addressing how oncogenic Ras expression perturbs proliferation, differentiation, and self-renewal programs in stem and progenitor cell populations, for testing potential therapies, and for investigating mechanisms of drug response and resistance. This review summarizes recent insights from key studies in mouse models of hematologic cancer that are broadly relevant for understanding Ras biology and for ongoing efforts to implement rational therapeutic strategies for cancers with oncogenic RAS mutations.