炎症促进实体瘤进展，但炎症调节机制如何影响白血病的研究还较少。使用膜联蛋白 A5 (ANXA 5) 作为模型系统，膜联蛋白 A5 是一种已知会导致细胞凋亡的钙结合蛋白，我们发现它在急性髓系 (AML) 小鼠和慢性髓系白血病小鼠的骨髓微环境 (BMM) 中存在差异表达，我们在这里揭示了一个回路，其中 AML 衍生的肿瘤坏死因子 (TNF)α 剂量依赖性地减少 BMM 中的 ANXA5。这会通过升高前列腺素 E2 (PGE2) 水平产生炎症性 BMM。通过与其 EP4 受体结合，PGE2 增加 AML 细胞中的 β-连环蛋白和缺氧诱导因子 (HIF) 1 α 信号传导，从而加速 PGE2 敏感的 AML。与其他血液恶性肿瘤相比，人类环钻活检可能显示 AML 中 ANXA5 表达较低，PGE2 表达较高。此外，同基因和异种移植模型表明，对于那些对 PGE2 高度敏感的 AML 类型，使用前列腺素内过氧化物合酶 2（环氧合酶 2 (COX2)）抑制剂、塞来昔布加阿糖胞苷治疗后，与单独使用阿糖胞苷相比，可提高生存率。总而言之，TNFα/ANXA5/NF-kB/COX2/PGE2 介导的炎症以高度差异和循环的方式影响 AML 病程，患有“炎症性 AML”的 AML 患者可能受益于抗炎药作为辅助治疗。版权所有 © 2024 美国协会血液学。

Inflammation promotes solid tumor progression, but how regulatory mechanisms of inflammation may impact leukemia is less well studied. Using annexin A5 (ANXA 5), a calcium-binding protein known for apoptosis, which we discovered to be differentially expressed in the bone marrow microenvironment (BMM) of mice with acute myeloid (AML) versus chronic myeloid leukemia, as a model system, we unravel here a circuit in which AML-derived tumor necrosis factor (TNF)α dose-dependently reduces ANXA5 in the BMM. This creates an inflammatory BMM via elevated levels of prostaglandin E2 (PGE2). Via binding to its EP4 receptor, PGE2 increases -catenin and hypoxia-inducible factor (HIF) 1 α signaling in AML cells, thereby accelerating PGE2-sensitive AML. Human trephine biopsies may show lower ANXA5 expression and higher PGE2 expression in AML compared to other hematological malignancies. Further, syngeneic and xenogeneic transplantation models suggest a survival benefit after treatment with the inhibitor of prostaglandin-endoperoxide synthase 2 (cyclooxygenase 2 (COX2)), celecoxib, plus cytarabine in those AML types highly sensitive to PGE2 compared to cytarabine alone. Taken together, TNFα/ANXA5/NF-kB/COX2/PGE2-mediated inflammation influences AML course in a highly differential and circular manner, and AML patients with 'inflammatory AML' may benefit from antiphlogistic agents as adjunct therapy.Copyright © 2024 American Society of Hematology.