骨髓微环境支持白细胞动员和分化并控制包括急性髓性白血病（AML）在内的白血病的发展。我们发现，具有骨吸收细胞Tsc1缺失的小鼠AML异种移植的发展被抑制。Tsc1缺陷骨吸收细胞释放大量的IL-34，有效诱导AML细胞分化，并在各种临床前模型中阻止AML进展。相反，IL-34缺乏的小鼠AML的发展加速。有趣的是，IL-34独立于其已知的受体抑制AML，而是直接结合到表达于髓系细胞上的关键信号中心——诱导受体表达的髓系细胞2（TREM2）。TREM2缺失的AML细胞和正常髓系细胞对IL-34治疗具有抗性。在机械上，IL-34-TREM2结合迅速磷酸化Rasal3，以消除ERK1/2信号并刺激分化，从而防止AML细胞增殖。此外，TREM2在AML患者中下调并与不良预后相关。该研究确定了TREM2作为IL-34的新受体，为克服AML患者中的AML分化阻断提供了有望的策略。 Copyright © 2023 American Society of Hematology。

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.Copyright © 2023 American Society of Hematology.