Systemic MIF facilitates chronic lymphocytic leukemia development independent of its cellular source

Abstract

Macrophage migration inhibitory factor (MIF) is broadly produced by various cell types, particularly immune cells, and functions as a key modulator of innate and adaptive immunity. Increasing evidence has linked MIF to the pathogenesis of both solid tumors and hematologic malignancies, including chronic lymphocytic leukemia (CLL). We previously showed that the global deletion of Mif in the TCL1 transgenic mouse model for CLL significantly delayed disease development leading to longer overall survival of the knockout mice. In this study, we demonstrated that adaptive transfer of murine CLL cells failed to establish disease in Mif-deficient recipients due to impaired homing of leukemic cells into the spleens, indicating that host-derived Mif is essential for leukemic infiltration and expansion. To identify the most relevant source of Mif in CLL, we generated two CLL mouse strains with B-lymphoid- or myeloid-lineage-specific Mif deletion. In contrast to the global Mif knockout, neither conditional Mif knockout significantly altered CLL progression, illustrating that the cellular source of Mif is less critical than its systemic presence in the tissue environment. Taken together, these in vivo findings indicate that MIF plays a relevant role in CLL pathogenesis, acting independently of its specific cellular origin. HighlightsO_LICLL cells failed to establish disease in Mif-deficient hosts due to impaired tissue homing C_LIO_LIConditional deletion of Mif in B lymphoid- or myeloid cells did not significantly impact CLL progression in vivo C_LIO_LISystemic MIF is critical for CLL pathogenesis, independent of its cellular source C_LI