Monocyte-Derived Leukemia-Associated Macrophages Facilitate Extramedullary Distribution of T-cell Acute Lymphoblastic Leukemia Cells

Macrophages play important roles in both physiologic and pathologic processes and arise from successive waves of embryonic and adult hematopoiesis. Monocyte-derived macrophages (MOMF) exert distinct functions under pathologic conditions, and leukemia-associated macrophages (LAM) show considerable diversities in activation and functional phenotype. However, their origin and pathologic roles have not been well elucidated. Here we used wild-type and CCR2(-/-) mice to study the pathologic 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. In the spleen, 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 mononu-clear cells. Moreover, Ly6C(+) LAM exhibited increased M1-related characteristics and contributed to sterile inflammation. In CCR2(-/-) leukemic mice, reduced Ly6C(+) LAM, relieved sterile inflammation, and reduced distribution of leukemia cells were detected in extramedullary tissues. In addition, 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 pathologic roles of monocyte-derived LAM in T-ALL progression. Significance: This study links monocyte-derived leukemia-associated macrophages with noninfectious inflammation and extramedullary distribution of leukemia cells during leukemia progression, providing new insight into macrophage-based immunotherapy in leukemia.