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

The bone marrow microenvironment supports leukocyte mobilization and differentia-tion 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 dif-ferentiation 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. Mech-anistically, 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 dif-ferentiation blockade in patients with AML.

Automated summary

The bone marrow microenvironment plays a crucial role in the development of acute myeloid leukemia (AML). This study found that mutated osteoclasts suppressed AML development by releasing high levels of interleukin-34 (IL-34), which promoted AML cell differentiation. This was achieved through the binding of IL-34 to triggering receptor expressed on myeloid cells 2 (TREM2), leading to the inhibition of AML progression.