Xian Wei, Chen Yinting, Yu Shuiqing, Ye Zhitao, Zhang Yu, Yao Danlin
Department of Pediatric Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
Department of Hematology, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
Front Immunol. 2025 May 1;16:1554231. doi: 10.3389/fimmu.2025.1554231. eCollection 2025.
Acute lymphoblastic leukemia (ALL) is a hematological malignancy with high survival rates in children; however, certain high-risk subtypes pose significant challenges due to poor prognosis and frequent relapse. Ubiquitination, a post-translational modification critical for protein regulation, has been implicated in various cancer processes, yet its role in ALL remains poorly understood.
Using the TARGET database, we identified molecular subtypes of ALL through consensus clustering based on ubiquitination-related genes (URGs). A nine-gene prognostic model was constructed using LASSO and Cox regression analyses. The immunological landscape variations between high- and low-risk groups were assessed using immune cell infiltration analysis and functional enrichment studies. was further explored through functional experiments and .
Four ALL subtypes with distinct survival outcomes were identified, with Cluster D representing the high-risk group. Patients were divided into high- and low-risk groups using the nine-gene predictive model, and was found to be a significant protective factor. According to immune landscape analysis, high-risk groups had an immunosuppressive microenvironment that was correlated with expression and marked by an increase in regulatory T cells and M2 macrophage infiltration. functional assays, knockdown notably enhanced cell proliferation and suppressed apoptosis in ALL cells. In -knockdown mouse models, investigations demonstrated increased tumor growth, reduced apoptosis, and diminished survival rates.
This work identifies as a crucial therapeutic target and prognostic biomarker for ALL. Knockdown of led to the suppression of apoptosis and increased tumor growth, suggesting potential therapeutic applications. These results highlight the need for more investigation into ubiquitination-related pathways and offer important new insights into high-risk ALL.
急性淋巴细胞白血病（ALL）是一种在儿童中具有高生存率的血液系统恶性肿瘤；然而，某些高危亚型由于预后不良和频繁复发而带来重大挑战。泛素化是一种对蛋白质调节至关重要的翻译后修饰，已涉及各种癌症过程，但其在ALL中的作用仍知之甚少。
利用TARGET数据库，我们通过基于泛素化相关基因（URGs）的共识聚类确定了ALL的分子亚型。使用LASSO和Cox回归分析构建了一个九基因预后模型。使用免疫细胞浸润分析和功能富集研究评估高危和低危组之间的免疫格局差异。通过功能实验进一步探索了 。
确定了四种具有不同生存结果的ALL亚型，其中聚类D代表高危组。使用九基因预测模型将患者分为高危和低危组，发现 是一个显著的保护因素。根据免疫格局分析，高危组具有免疫抑制微环境，与 表达相关，并以调节性T细胞和M2巨噬细胞浸润增加为特征。 功能测定显示， 敲低显著增强了ALL细胞的增殖并抑制了凋亡。在 敲低小鼠模型中， 研究表明肿瘤生长增加、凋亡减少且生存率降低。
这项工作确定 为ALL的关键治疗靶点和预后生物标志物。 敲低导致凋亡抑制和肿瘤生长增加，提示潜在的治疗应用。这些结果凸显了对泛素化相关途径进行更多研究的必要性，并为高危ALL提供了重要的新见解。
