Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the nucleophosmin 1 ( NPM1 ) -ALK fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of FMS-like tyrosine kinase mutation–positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinib-mediated growth inhibitory effects on NPM1-ALK–driven ALCL cells. We utilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib-mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of proapoptotic protein BAD, and decreased expression of antiapoptotic proteins, survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell-cycle analysis indicated gilteritinib induced G–G1-phase cell-cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK fusion–driven hematologic or solid malignancies. Implications: Our preclinical results explore the use of gilteritinib for the treatment of NPM1-ALK–driven ALCL cells and pave a path for developing future clinical trials. Visual Overview: .

中文翻译：

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Gilteritinib 对 NPM1-ALK 驱动的间变性大细胞淋巴瘤细胞的临床前评价

间变性大细胞淋巴瘤（ALCL）是一种侵袭性非霍奇金淋巴瘤。由于 t(2;5) 染色体易位，超过四分之三的间变性淋巴瘤激酶 (ALK) 阳性 ALCL 病例表达核磷蛋白 1 ( NPM1 ) -ALK 融合基因。NPM1-ALK 融合蛋白的同二聚化介导嵌合酪氨酸激酶活性的组成型激活和负责淋巴瘤细胞增殖和存活的下游信号通路。Gilteritinib 是一种酪氨酸激酶抑制剂，最近被 FDA 批准用于治疗 FMS 样酪氨酸激酶突变阳性的急性髓细胞白血病。在这项研究中，我们首次证明了 gilteritinib 介导的对 NPM1-ALK 驱动的 ALCL 细胞的生长抑制作用。我们总共使用了五种 ALCL 模型细胞系，包括人和鼠。Gilteritinib 治疗抑制 NPM1-ALK 融合激酶磷酸化和下游信号传导，导致诱导细胞凋亡。Gilteritinib 介导的细胞凋亡与半胱天冬酶 3/9、PARP 裂解、促凋亡蛋白 BAD 的表达增加以及抗凋亡蛋白、survivin 和 MCL-1 的表达降低有关。我们还发现融合激酶活性的下调导致 c-Myc 蛋白水平降低。此外，细胞周期分析表明 gilteritinib 诱导 G-G1 期细胞周期停滞并降低 CD30 表达。总之，我们的临床前研究探索了 gilteritinib 在治疗表达 NPM1-ALK 的 ALCL 细胞以及其他 ALK 或 ALK 融合驱动的血液或实体恶性肿瘤中的新治疗潜力。影响：我们的临床前结果探索了使用 gilteritinib 治疗 NPM1-ALK 驱动的 ALCL 细胞，并为开发未来的临床试验铺平了道路。视觉概览：.