弥漫性大B细胞淋巴瘤(DLBCL)具有高度的分子和临床异质性。自噬是一种以溶酶体驱动的分解过程，致力于维持正常造血干细胞和前体细胞的稳态，其失调在造血系统恶性肿瘤的发生和发展中起关键作用。自噬的一个主要调控因子是BECLIN-1，它可以与BCL-2或PI3KC3交互作用，分别促使细胞凋亡或自噬。BCL2和BECN1的表达变化与淋巴瘤的预后密切相关，但其是否与自噬和凋亡之间的失调交互作用有关尚待阐明。TCGA数据库分析显示，在DLBCL患者中，BCL2和BECN1的mRNA表达呈负相关。在暴露于多柔比星的典型DLBCL细胞系中，高表达BCL-2的细胞对药物具有耐药性，而高表达BECLIN-1的细胞对药物具有敏感性，这与自噬通量低和高相关。靶向BCL-2的Venetoclax增加了细胞对多柔比星的敏感性，而抑制BECLIN-1依赖性自噬的spautin-1则对先前的情况具有相反的效果。通过对TCGA DLBCL数据集进行分析，我们发现BCL2和BECN1在DLBCL中分别作为负和正预后标志。通过对各个队列的差异表达基因分析发现，BCL2与致癌途径（例如葡萄糖转运途径、HIF1A信号通路、JAK-STAT信号通路、PI3K-AKT-mTOR通路）呈正相关，与自噬相关转录本呈负相关，而BECN1则呈相反的趋势。值得注意的是，高表达BECN1的患者显示较长的生存期。我们的数据首次揭示了BECLIN-1依赖性自噬调节对DLBCL患者预后的影响，并提供了支持利用通过刺激自噬来增强淋巴瘤细胞对化疗药物敏感性的治疗用药的机制解释。

Diffuse large B-cell lymphoma (DLBCL) is characterized by high molecular and clinical heterogeneity. Autophagy, a lysosome-driven catabolic process devoted to macromolecular turnover, is fundamental in maintaining normal hematopoietic stem cells and progenitors homeostasis, and its dysregulation plays a critical role in the initiation and progression of hematological malignancies. One main regulator of autophagy is BECLIN-1, which may interact alternatively with either BCL-2, thus allowing apoptosis, or PI3KC3, thus promoting autophagy. The altered expression of BCL2 and BECN1 correlates with lymphoma outcomes, but whether this is associated with dysregulated cross-talk between autophagy and apoptosis remains to be elucidated. Analysis of the TCGA database revealed that BCL2 and BECN1 mRNA expression were inversely correlated in DLBCL patients. In representative DLBCL cell lines exposed to doxorubicin, the cells highly expressing BCL-2 were resistant, while the ones highly expressing BECLIN-1 were sensitive, and this correlated with low and high autophagy flux, respectively. Venetoclax targeting of BCL-2 increased while the spautin-1-mediated inhibition of BECLIN-1-dependent autophagy reversed doxorubicin sensitivity in the former and in the latter, respectively. By interrogating the TCGA DLBCL dataset, we found that BCL2 and BECN1 acted as negative and positive prognostic markers for DLBCL, respectively. The differentially expressed gene analysis in the respective cohorts revealed that BCL2 positively correlated with oncogenic pathways (e.g., glucose transport, HIF1A signaling, JAK-STAT signaling, PI3K-AKT-mTOR pathway) and negatively correlated with autophagy-related transcripts, while BECN1 showed the opposite trend. Notably, patients with high BECN1 expression displayed longer survival. Our data reveal, for the first time, that the modulation of BECLIN-1-dependent autophagy influences the prognosis of DLBCL patients and provide a mechanistic explanation supporting the therapeutic use of drugs that, by stimulating autophagy, can sensitize lymphoma cells to chemotherapy.