CD69 Blockade Restores the Bone Marrow Niche and Delays Leukemogenesis in a Mouse Model of NrasG12D-driven Chronic Myelomonocytic Leukemia

A subset of patients with chronic myelomonocytic leukemia (CMML) carry NRAS mutations, which are associated with shorter overall survival and higher risk of leukemic transformation. The precise impact of NRAS mutations on the bone marrow microenvironment (BME) remains unclear. In a mouse model of CMML induced by a single Nras ^G12D allele mutation, we observed increased infiltration of regulatory T (Treg) cells and CD69 ⁺ T cells within the BME, whereas CD69 expression on peripheral blood T cells remained low compared to T cells in the bone marrow. We administered an anti-CD69 monoclonal antibody to Nras ^G12D -mutated CMML mice to investigate whether CD69 caused BME immune suppression. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing revealed that anti-CD69 monoclonal antibody treatment prevented granulocyte-macrophage progenitor cells generation, prolonged CMML mouse survival, and decreased BME Tregs. Our data indicate that CD69 may be a biomarker for BME immunological dysfunction in CMML.