The current clinical management of Extranodal NK/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the PINK-E prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown (KD) in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA-sequencing (RNA-seq) used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-seq data upon MYC KD with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.

中文翻译：

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自然杀伤细胞淋巴瘤中 MYC 过度表达：预后和治疗意义。

目前结外 NK/T 细胞淋巴瘤 (ENKTL) 的临床治疗主要依赖于常规化疗和放疗，因此需要创新的治疗策略。本研究探讨 c-MYC (MYC) 在 ENKTL 中的临床意义和治疗意义。最初，我们在 111 名患者的大队列中约 75% 的病例中发现了 MYC 蛋白过度表达。 MYC 过度表达与淋巴瘤细胞增殖和不良临床结果密切相关。有趣的是，将 MYC 表达整合到 PINK-E 预后模型中显着增强了其预测能力。随后，我们在 MYC 过表达的 NK 恶性肿瘤细胞系中实施了 MYC 敲低（KD），导致存活率显着降低。用于确定 MYC 功能的 RNA 测序 (RNA-seq) 揭示了与经典 MYC 调节基因的高度重叠以及代谢和细胞周期调节的富集。对 MYC KD 的 RNA-seq 数据与原发性 ENKTL 病例的基因表达谱进行综合分析，确定了与 MYC 过度表达密切相关的基因子集。其中，CDK4成为潜在的治疗靶点，其抑制不仅消除了MYC功能，还降低了NK恶性肿瘤细胞中MYC的表达。此外，临床级 CDK4/6 抑制剂 palbociclib 在异种移植小鼠模型中表现出有效的抗肿瘤作用，特别是与吉西他滨联合使用时。总之，我们的研究牢固地确立了 MYC 作为 ENKTL 中具有预后意义的癌基因，并强调 CDK4 抑制是治疗 MYC 过表达的 ENKTL 的一种有前途的治疗策略。