Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell nonautonomous pathways may help overcome resistance to targeted therapies. Herein we leverage genetic mouse models, patient-derived xenografts, and patient samples to show that acute myeloid leukemia (AML) exploits peripheral serotonin signaling to remodel the endosteal niche to its advantage. AML progression requires the presence of serotonin receptor 1B (HTR1B) in osteoblasts and is driven by AML-secreted kynurenine, which acts as an oncometabolite and HTR1B ligand. AML cells utilize kynurenine to induce a proinflammatory state in osteoblasts that, through the acute-phase protein serum amyloid A (SAA), acts in a positive feedback loop on leukemia cells by increasing expression of IDO1—the rate-limiting enzyme for kynurenine synthesis—thereby enabling AML progression. This leukemia–osteoblast cross-talk, conferred by the kynurenine–HTR1B–SAA–IDO1 axis, could be exploited as a niche-focused therapeutic approach against AML, opening new avenues for cancer treatment. Significance: AML remains recalcitrant to treatments due to the emergence of resistant clones. We show a leukemia-cell nonautonomous progression mechanism that involves activation of a kynurenine–HTR1B–SAA–IDO1 axis between AML cells and osteoblasts. Targeting the niche by interrupting this axis can be pharmacologically harnessed to hamper AML progression and overcome therapy resistance. This article is highlighted in the In This Issue feature, p. 873

中文翻译：

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犬尿氨酸颠覆成骨细胞中的血清素受体信号传导导致急性髓系白血病

肿瘤细胞重塑微环境可以激活有利于癌症生长的途径。对此类恶性细胞非自主途径的分子描述和靶向可能有助于克服对靶向治疗的耐药性。在此，我们利用遗传小鼠模型、患者来源的异种移植物和患者样本来证明急性髓系白血病（AML）利用外周血清素信号传导来重塑骨内膜生态位以发挥其优势。AML 进展需要成骨细胞中存在血清素受体 1B (HTR1B)，并由 AML 分泌的犬尿氨酸驱动，犬尿氨酸充当肿瘤代谢物和 HTR1B 配体。AML 细胞利用犬尿氨酸在成骨细胞中诱导促炎状态，通过急性期蛋白血清淀粉样蛋白 A (SAA)，通过增加 IDO1（犬尿氨酸合成的限速酶）的表达，对白血病细胞产生正反馈循环作用。从而促进 AML 的进展。这种由犬尿氨酸-HTR1B-SAA-IDO1轴赋予的白血病-成骨细胞串扰可被用作针对AML的针对利基市场的治疗方法，为癌症治疗开辟新途径。意义：由于耐药克隆的出现，AML 仍然难以接受治疗。我们展示了白血病细胞非自主进展机制，涉及 AML 细胞和成骨细胞之间的犬尿氨酸 - HTR1B - SAA - IDO1 轴的激活。通过中断该轴来靶向利基可以在药理学上阻碍 AML 进展并克服治疗耐药性。这篇文章在本期特稿中重点介绍，第 17 页。第873章