髓系白血病
癌症研究
髓样
白血病
受体
生物
免疫学
医学
内科学
作者
Xiaoling Xie,Wuju Zhang,Min Xiao,Tiantian Wei,Qiu Yu-chang,Jingyang Qiu,Hao Wang,Zeyou Qiu,Sheng Zhang,Yating Pan,Linlin Mao,Yuhua Li,Bin Guo,Wanwen Yang,Yuxing Hu,Shujie Hu,Yan Gong,Jun Yang,Guozhi Xiao,Yue Zhang,Xiaochun Bai
出处
期刊:Blood
[American Society of Hematology]
日期:2023-03-31
被引量:11
标识
DOI:10.1182/blood.2022018619
摘要
The bone marrow microenvironment supports leukocyte mobilization and differentiation and controls the development of leukemias, including acute myeloid leukemia (AML). Here, we found that the development of AML xenotransplants was suppressed in mice with osteoclasts Tsc1 deletion. Tsc1-deficient osteoclasts released a high level of IL-34, which efficiently induced AML cell differentiation and prevented AML progression in various preclinical models. Conversely, AML development was accelerated in IL-34-deficient mice. Interestingly, IL-34 inhibited AML independent of its known receptors, but bound directly to triggering receptor expressed on myeloid cells 2 (TREM2), a key hub of immune signals. TREM2-deficient AML cells and normal myeloid cells were resistant to IL-34 treatment. Mechanistically, IL-34-TREM2 binding rapidly phosphorylated Rasal3 and inactivated ERK1/2 signaling to prevent AML cell proliferation and stimulate differentiation. Furthermore, TREM2 was downregulated in AML patients and associated with a poor prognosis. This study identified TREM2 as a novel receptor for IL-34, indicating a promising strategy for overcoming AML differentiation blockade in AML patients.
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