Phagocytosis activity is retained by JMML macrophages and increased by CD47 inhibition

Summary Juvenile myelomonocytic leukaemia (JMML) is a childhood myeloid malignancy driven by RAS (rat sarcoma viral oncogene homolog) pathway mutations, characterized by myeloid cell accumulation and organ infiltration. We investigated how clonal macrophage polarization, phagocytic function and CD47 (cluster of differentiation 47) expression contribute to immune dysregulation. Human PTPN11 (protein tyrosine phosphatase non‐receptor type 11) ‐mutated JMML spleens exhibited higher M1‐like macrophage levels than KRAS (KRAS proto‐oncogene, GTPase)‐mutated cases or controls. Both human JMML macrophages and murine cells from Mx‐Cre;Ptpn11 D61Y/+ mice retained phagocytic activity, with M1‐like cells being the most active. CD47, a ‘don't eat me’ signal, was upregulated in human and murine JMML cells; its blockade enhanced in vitro phagocytosis. In a patient‐derived xenograft model, the CD47 inhibitor magrolimab reduced leukaemia burden in the spleen but not the bone marrow. No synergy was observed between magrolimab and azacitidine. These findings demonstrate that clonal JMML macrophages retain phagocytic activity and contribute to an inflammatory phenotype. While CD47 blockade shows limited therapeutic potential, this study clarifies the interplay between macrophage polarization, immune evasion and inflammation, providing a basis for future JMML strategies.