Chronic myelomonocytic leukemia (CMML) is a devastating cancer that primarily occurs in the elderly with the median age ranging from 65 to 75 years. CMML is characterized by persistent monocytosis in peripheral blood. The clinical phenotypes of CMML are heterogeneous, ranging from predominantly myeloproliferative (MP-CMML) to predominantly myelodysplastic (MD-CMML). Approximately 15-20% of CMML cases evolve to acute myeloid leukemia (AML) soon after their initial diagnosis. The prognosis of CMML is poor with the median survival ranging from 15 to 20 months. Oncogenic NRAS mutations are frequently indentified in CMML patients, especially in patients with MP-CMLL. Consistent with human studies, our lab previously developed a MP-CMML mouse model induced by NrasG12D/+ expressed from its endogenous locus. Over 90% of recipient mice transplanted with NrasG12D/+ bone marrow cells develop MP-CMML-like phenotypes with a prolonged latency. In this mouse model, NrasG12D/+-HSCs are leukemia initiating cells (LICs). And hyperactivation of granulocyte-macrophage colony stimulating factor (GM-CSF) signaling, which is frequently associated with human CMML patients, is acquired during CMML progression. These results suggest that hyperactivation of GM-CSF signaling might be essential for CMML initiation and/or progression. To further test this hypothesis, we deleted GM-CSF receptor βc subunit in NrasG12D/+ mice. Our results indicate that deletion of βc abolishes GM-CSF signaling, but neither affects NrasG12D/+ HSC functions, nor abrogates NrasG12D/+-induced CMML. However, loss of βc-mediated GM-CSF signaling did slow down CMML progression, as demonstrated by reduced splenmegaly, loss of spontaneous colony formation, and prolonged the survival of recipient mice with NrasG12D/+ cells. Together, our data suggest that inhibiting GM-CSF signaling in MP-CMML patients might transiently mitigate disease phenotypes but not eradicate the disease. NrasG12D/+-induced CMML in mice never spontaneously transform to AML. We tested the potential genetic interaction between loss of p53 and endogenous oncogenic Nras signaling in promoting CMML to AML. For this purpose, we generated conditional NrasG12D/+; p53-/- mice. The recipient mice transplanted with NrasG12D/+; p53-/- bone marrow cells developed a highly penetrant AML. Our results demonstrate that loss of p53 profoundly impacts on NrasG12D/+ MPs to promote leukemogenesis, as demonstrated by increased quiescence and self-renewal in NrasG12D/+; p53-/- MPs. These mutant MPs are transformed to AML initiating cells (referred as AML-MPs). The distinct transcriptome of AML-MPs is mainly driven by loss of p53. Moreover, oncogenic Nras is overexpressed in AML-MPs through genetic and epigenetic mechanisms leading to hyperactivation of ERK1/2 signaling. Together, our results indicate that loss of p53 synergizes with enhanced oncogenic Nras signaling to promote the leukemogenic transformation of MPs and drive the evolution of CMML to AML.