TREM2 acts as a receptor for IL-34 to suppress acute myeloid leukemia in mice

Xiaoling Xie, Wuju Zhang, Min Xiao, Tiantian Wei, Yingqi Qiu, 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

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 tuberous sclerosis 1 (Tsc1) deletion. Tsc1-deficient osteoclasts released a high level of interleukin-34 (IL-34), which efficiently induced AML cell differentiation and prevented AML progression in various preclinical models. Conversely, AML development was accelerated in mice deficient in IL-34. 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 Ras protein activator like 3 and inactivated extracellular signal-regulated protein kinase 1/2 signaling to prevent AML cell proliferation and stimulate differentiation. Furthermore, TREM2 was downregulated in patients with AML 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 patients with AML.

Original languageEnglish
Pages (from-to)3184-3198
Number of pages15
JournalBlood
Volume141
Issue number26
DOIs
Publication statusPublished - 29 Jun 2023
Externally publishedYes

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