Monocyte-derived leukemia-associated macrophages facilitate extramedullary distribution of T-cell acute lymphoblastic leukemia cells

Feifei Yang, Wenli Feng, Hao Wang, Lina Wang, Xiaoli Liu, Rong Wang, Chong Chen, Xiao Yang, Dongyue Zhang, Qian Ren, Guoguang Zheng
2020 Cancer Research  
Macrophages play important roles in both physiological and pathological processes and arise from successive waves of embryonic and adult hematopoiesis. Monocyte-derived macrophages (MOMF) exert distinct functions under pathological conditions, and leukemia-associated macrophages (LAM) show considerable diversities in activation and functional phenotype. However, their origin and pathological roles have not been well elucidated. Here we used wild-type (WT) and CCR2-/- mice to study the
more » ... study the pathological roles of monocyte-derived LAM in extramedullary tissues in models of Notch1-induced T-cell acute lymphoblastic leukemia (T-ALL). MOMF existed in the resting liver and spleen (SP). In SP, Ly6C+ monocytes gave rise to the Ly6C+ macrophage subset. Furthermore, an increase of monocyte-derived LAM, including the Ly6C+ subset, was detected in the extramedullary tissues in leukemic mice. More monocyte-derived LAM, including Ly6C+ LAM, was detected in the spleens of leukemic mice transplanted with exogeneous mononuclear cells. Moreover, Ly6C+ LAM exhibited increased M1-related characteristics and contributed to sterile inflammation. In CCR2-/- leukemic mice, reduced Ly6C+ LAM, relived sterile inflammation, and reduced distribution of leukemia cells were detected in extramedullary tissues. Additionally, monocyte-derived Ly6C+ LAM expressed high levels of CCL8 and CCL9/10. Blocking CCR1 and CCR2 relieved hepatosplenomegaly and inhibited the extramedullary distribution of leukemia cells in T-ALL mice. Collectively, our findings reveal the multifaceted pathological roles of monocyte-derived LAM in T-ALL progression.
doi:10.1158/0008-5472.can-20-0034 pmid:32651260 fatcat:rxowve7yvvh23be2o26trjw3ji