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

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 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.

IL-34 and its receptors as predictors of brain metastasis and prognosis in lung adenocarcinoma: Unveiling insights through bioinformatic and immunohistochemical investigations

“…It is noteworthy that as research on IL-34 advances, additional receptors for IL-34 besides CSF-1R, SDC-1, and PTPRZ1 may be discovered. For instance, TREM2 has recently been identified as an additional receptor for IL-34 [ 17 ]. Exploring the relationship between these novel receptors of IL-34 and poor prognosis in patients with LUAD could enhance our understanding of the role of IL-34 in LUAD.…”

Interleukin-34-NF-κB signaling aggravates myocardial ischemic/reperfusion injury by facilitating macrophage recruitment and polarization

“…One caveat regrading this discrepancy would be attributed to the differing binding receptors of CSF1 and IL-34. Although these two ligands can interact with CSF-1R, IL-34 has a lower affinity and correspondingly lower activity than CSF1, moreover, researches have revealed that IL-34 could specifically interact with PTPRZ, 28 SDC1, 57 and TREM2, 58 which may elicit differential signaling cascades and consequences. Collectively, our data revealed that IL-34 exhibited a nonredundant, CSF1-independent role in the progression of cardiac remodeling after IR.…”

Mechanisms of TREM2 mediated immunosuppression and regulation of cancer progression

“…Besides, in acute myeloid leukemia (AML), TREM2, as a novel receptor for IL-34, can induce myeloid differentiation and inhibit AML progression by inhibiting the ERK1/2/Rasal3 signaling pathway. On the contrary, TREM2 gene-deficient AML cells and normal myeloid cells exhibit resistance to IL-34 treatment and are associated with poor prognosis ( 59 ). These findings suggest that TREM2 can inhibit tumorigenesis and development by activating different signaling pathways and plays an important tumor suppressor role.…”