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

The bone marrow microenvironment supports leukocyte mobilization and differentiation and 10 controls the development of leukemias, including acute myeloid leukemia (AML). Here, we 11 found that the development of AML xenotransplants was suppressed in mice with osteoclasts 12 Tsc1 deletion. Tsc1-deficient osteoclasts released a high level of IL-34, which efficiently 13 induced AML cell differentiation and prevented AML progression in various preclinical 14 models. Conversely, AML development was accelerated in IL-34-deficient mice. Interestingly, 15 IL-34 inhibited AML independent of its known receptors, but bound directly to triggering 16 receptor expressed on myeloid cells 2 (TREM2), a key hub of immune signals. 17 TREM2-deficient AML cells and normal myeloid cells were resistant to IL-34 treatment. 18 Mechanistically, IL-34–TREM2 binding rapidly phosphorylated Rasal3 and inactivated 19 ERK1/2 signaling to prevent AML cell proliferation and stimulate differentiation. 20 Furthermore, TREM2 was downregulated in AML patients and associated with a poor 21 prognosis. This study identified TREM2 as a novel receptor for IL-34, indicating a promising 22 strategy for overcoming AML differentiation blockade in AML patients.