IL-21/IL-21R 信号使急性髓性白血病干细胞更易受阿糖胞苷治疗和 CAR T 细胞疗法的影响。

IF 11.7 1区医学 Q1 CELL BIOLOGY Cell Reports Medicine Pub Date : 2024-11-08 DOI:10.1016/j.xcrm.2024.101826

Viviana Rubino, Michelle Hüppi, Sabine Höpner, Luigi Tortola, Noah Schnüriger, Hugo Legenne, Lea Taylor, Svenja Voggensperger, Irene Keller, Remy Bruggman, Marie-Noëlle Kronig, Ulrike Bacher, Manfred Kopf, Adrian F Ochsenbein, Carsten Riether

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引用次数: 0

摘要

白血病干细胞（LSCs）的自我更新程序预示着急性髓性白血病（AML）患者的不良预后。我们发现CD4+ T细胞衍生的白细胞介素（IL）-21是白血病干细胞自我更新的重要负调控因子。IL-21/IL-21R信号通过激活p38-MAPK信号有利于LSCs的不对称细胞分裂和分化，从而导致LSC数量减少，并显著延长了小鼠AML模型的存活时间。在人类急性髓细胞性白血病中，诊断时的血清IL-21被确定为独立的阳性预后生物标志物，并与接受大剂量化疗的患者生存率提高和完全缓解率升高相关。IL-21 治疗可抑制原发性 LSC 功能，并增强体外阿糖胞苷和 CD70 CAR T 细胞治疗对 LSC 的作用。低剂量IL-21治疗可延长AML小鼠在合成和异种移植实验中的存活时间。因此，促进LSCs上的IL-21/IL-21R信号转导可能是减少AML干性和增加分化的一种方法。

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IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy.

Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4⁺ T cell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR T cell treatment on LSCs in vitro. Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML.

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.