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

Abstract

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 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 TALL mice. Collectively, our findings reveal the multifaceted pathological roles of monocyte-derived LAM in TALL progression.

Integrin signaling is critical for myeloid-mediated support of T-cell acute lymphoblastic leukemia

“…These findings suggest that tumor-associated myeloid cells may activate FAK and PYK2 in T-ALL cells not only through integrin signaling, but also through additional pathways. A previous study reported that Vegfa and Il1b transcripts are elevated in leukemia-associated macrophages in a NOTCH1-induced model of T-ALL (57), suggesting secreted myeloid factors could promote FAK/PYK2 activation in T-ALL cells. Thus, a better understanding of the mechanisms by which tumor-associated myeloid cells activate FAK and PYK2 signaling and how these pathways contribute to T-ALL progression could reveal therapeutic opportunities in T-ALL.…”

DDIT4 mediates the proliferation-promotive effect of IL-34 in human monocytic leukemia cells

“…Wright staining was performed following the standard protocols. 36 The morphology of cells was detected under a light microscope (AXIO Observer A1, Germany).…”

Contribution of Extramedullary Hematopoiesis to Atherosclerosis. The Spleen as a Neglected Hub of Inflammatory Cells

“…This change in the hematopoietic topographic hierarchy during inflammation entails important biological, diagnostic and therapeutic implications. Monocytes from extramedullary tissues, such as the spleen, belong to the inflammatory subset (Ly-6C high ) and express proinflammatory factors, including reactive oxygen species and proteases (80,133,134). They accumulate in developing lesions, favoring an enhanced lipid intake and hypercholesterolemia that lead to atheroma progression.…”