Endogenous Oncogenic Nras Mutation Leads to Aberrant GM-CSF Signaling In Granulocytic/Monocytic Precursors In a Murine Model of Chronic Myelomonocytic Leukemia

Abstract 4180

Oncogenic NRAS mutations are frequently identified in myeloid diseases involving monocyte lineage. However, its role in the genesis of these diseases remains elusive. We report a mouse bone marrow transplantation model harboring an oncogenic G12D mutation in the Nras locus. Approximately 95% of recipient mice develop a myeloproliferative disease resembling the myeloproliferative variant of chronic myelomonocytic leukemia (CMML), with a prolonged latency and acquisition of multiple genetic alterations, including uniparental disomy of oncogenic Nras allele. Based on single-cell profiling of phospho-proteins, a novel population of CMML cells is identified to display aberrant GM-CSF signaling in both the ERK1/2 and Stat5 pathways. This abnormal signaling is acquired during CMML development. Further study suggests that aberrant Ras/ERK signaling leads to expansion of granulocytic/monocytic precursors, which are highly responsive to GM-CSF. Hyperactivation of Stat5 in CMML cells is mainly through expansion of these precursors rather than upregulation of surface expression of GM-CSF receptor. Our results provide insights into the aberrant cytokine signaling in oncogenic Nras-associated myeloid diseases. Our mouse model will serve as a powerful system to identify and validate cooperating mutations of oncogenic Nras in myeloid leukemias as well as assess the therapeutic efficacy of molecular agents in treating these leukemias.