ABSTRACT Chronic myelomonocytic leukemia (CMML) is a devastating cancer for which there is currently no effective therapy. Approximately 20% of CMML cases evolve to acute myelogenous leukemia (AML) soon after their initial diagnosis, contributing to the poor prognosis of CMML patients (median survival: ~20 months). While recent sequencing efforts identified numerous genetic mutations in CMML, translating these genomic data into physiological mechanisms and therapeutics remains very challenging. This challenge arises from the incomplete genetic/epigenetic landscape of CMML and limitations to mechanistically define genetic interactions of various mutations. Studies during the prior funding period leveraged our innovative CMML mouse model induced by endogenous oncogenic Nras (NrasG12D/+). Based on our recent results from this and its derived models as well as results from whole exome sequencing of patient samples, we hypothesize that the genetic interaction between oncogenic Ras signaling and mutations in epigenetic regulators forms a positive feedback loop to further strengthen the signaling network and select for additional mutations in epigenetic regulators during CMML progression and transformation to AML. Therefore, effective targeting of oncogenic Ras signaling or simultaneous targeting Ras signaling and aberrant epigenetic landscape could be promising therapeutic strategies against CMML progression, transformation to AML, and/or AML progression. As a part of our long-term goal to understand the molecular and cellular mechanisms in tumor initiation, progression, and malignant transformation, in this application we propose: 1) To determine how NrasG12D cooperates with mutations in epigenetic regulators to promote CMML development; 2) To determine whether combined therapies effectively control CMML progression, transformation to AML, and/or AML progression in vivo. Successful accomplishment of the proposed studies will not only provide insights into the initiation, progression and transformation of CMML, but may also lead to novel insights into myeloid diseases with RAS pathway mutations and mutations in epigenetic regulators in general.