TREM2 acts as a receptor for IL-34 to suppress acute myeloid leukemia in mice.
Blood
; 141(26): 3184-3198, 2023 06 29.
Article
em En
| MEDLINE
| ID: mdl-37001042
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
Limite:
Animals
Idioma:
En
Revista:
Blood
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China