Monocyte-Derived Leukemia-Associated Macrophages Facilitate Extramedullary Distribution of T-cell Acute Lymphoblastic Leukemia Cells
Monocyte-Derived Leukemia-Associated Macrophages Facilitate Extramedullary Distribution of T-cell Acute Lymphoblastic Leukemia Cells
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单核细胞来源的白血病相关巨噬细胞促进 T 细胞急性淋巴细胞白血病细胞的髓外分布。
DOI：
10.1158/0008-5472.can-20-0034
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发表时间：
2020-09-01
期刊：
影响因子：
11.2
通讯作者：
Zheng, Guoguang
中科院分区：
文献类型：
--
作者：
Yang, Feifei;Feng, Wenli;Zheng, Guoguang
巨噬细胞在生理和病理过程中起重要作用，是胚胎和成体造血连续波的产物。单核细胞源性巨噬细胞（MOMF）在病理状态下发挥独特的功能，而白血病相关巨噬细胞（LAM）在活化和功能表型上表现出相当大的差异。然而，它们的起源和病理作用尚未得到很好的阐明。在这里，我们使用野生型和CCR 2（-/-）小鼠研究单核细胞来源的LAM在Notch 1诱导的T细胞急性淋巴细胞白血病（T-ALL）模型髓外组织中的病理作用。MOMF存在于静息的肝脏和脾脏中。在脾脏中，Ly 6C（+）单核细胞产生Ly 6C（+）巨噬细胞亚群。此外，在白血病小鼠的髓外组织中检测到单核细胞来源的LAM（包括Ly 6C（+）亚群）增加。在移植外源性单核细胞的白血病小鼠的脾脏中检测到更多的单核细胞来源的LAM，包括Ly 6C（+）LAM。此外，Ly 6C（+）LAM表现出增加的M1相关特征，并导致无菌性炎症。在CCR 2（-/-）白血病小鼠中，在髓外组织中检测到Ly 6C（+）LAM减少，无菌炎症减轻，白血病细胞分布减少。此外，单核细胞来源的Ly 6C（+）LAM表达高水平的CCL 8和CCL 9/10。阻断CCR 1和CCR 2可减轻T-ALL小鼠的肝脾肿大并抑制白血病细胞的髓外分布。总的来说，我们的研究结果揭示了单核细胞衍生的LAM在T-ALL progress.Significance的多方面病理作用：这项研究将单核细胞衍生的白血病相关巨噬细胞与白血病进展过程中的非感染性炎症和白血病细胞的髓外分布联系起来，为基于巨噬细胞的白血病免疫治疗提供了新的见解。
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.