State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Department of Anesthesiology, Beijing Hospital, National Center of Gerontology, Beijing, China.
Cytotherapy. 2020 Mar;22(3):127-134. doi: 10.1016/j.jcyt.2020.01.001. Epub 2020 Feb 3.
Enhanced interleukin-1β (IL-1β) signaling is a common event in patients with acute myeloid leukemia (AML). It was previously demonstrated that chronic IL-1β exposure severely impaired hematopoietic stem cell (HSC) self-renewal capability in mice and promoted leukemia cell growth in primary AML cells. However, the role of IL-1β in the murine bone marrow (BM) niche remains unclear. Here, we explored the role of IL-1β in the BM niche in Il-1r1 mice, chronic IL-1β exposure mice and mixed lineage leukemia-AF9 fusion gene (MLL-AF9)-induced AML mice models. We demonstrated that IL-1R1 deficiency did not affect the function of HSCs or niche cells under steady-state conditions or during transplantation. Chronic exposure to IL-1β decreased the expansion of Il-1r1 hematopoietic cells in Il-1r1 recipient mice. These results indicated that IL-1β exposure impaired the ability of niche cells to support hematopoietic cells. Furthermore, we revealed that IL-1R1 deficiency in niche cells prolonged the survival of MLL-AF9-induced AML mice. The results of our study suggest that inhibition of the IL-1β/IL-1R1 signaling pathway in the niche might be a non-cell-autonomous therapy strategy for AML.
白细胞介素-1β（IL-1β）信号的增强是急性髓系白血病（AML）患者的常见事件。先前的研究表明，慢性 IL-1β 暴露严重损害了小鼠造血干细胞（HSC）的自我更新能力，并促进了原发性 AML 细胞中的白血病细胞生长。然而，IL-1β 在小鼠骨髓（BM）龛中的作用仍不清楚。在这里，我们在 Il-1r1 小鼠、慢性 IL-1β 暴露小鼠和混合谱系白血病-AF9 融合基因（MLL-AF9）诱导的 AML 小鼠模型中探索了 IL-1β 在 BM 龛中的作用。我们证明，在稳态条件下或移植期间，IL-1R1 缺失不影响 HSCs 或龛细胞的功能。慢性 IL-1β 暴露会降低 Il-1r1 受体小鼠中 Il-1r1 造血细胞的扩增。这些结果表明，IL-1β 暴露损害了龛细胞支持造血细胞的能力。此外，我们揭示了龛细胞中 IL-1R1 的缺失延长了 MLL-AF9 诱导的 AML 小鼠的存活时间。我们的研究结果表明，抑制龛细胞中的 IL-1β/IL-1R1 信号通路可能是 AML 的一种非细胞自主治疗策略。
