High BECN1 Expression Negatively Correlates with BCL2 Expression and Predicts Better Prognosis in Diffuse Large B-Cell Lymphoma: Role of Autophagy

Abstract

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.

Insights into Autophagic Machinery and Lysosomal Function in Cells Involved in the Psoriatic Immune-Mediated Inflammatory Cascade

“…On the other hand, intervention by autophagy activator rapamycin or inhibitor 3-MA, both targeting at mTOR, accordingly induced activation or inhibition of apoptosis; intervention by MK-3903 or dorsomorphin, activator or inhibitor of 5ꞌAMP-activated protein kinase (AMPK), received similar results (Chen et al 2023). One of the main regulators of autophagy, BECLIN-1 may interact alternatively with either BCL-2, thus allowing apoptosis, or PI3KC3, thus promoting autophagy (Salwa et al 2023). Dysregulation of UNC-like autophagy activating kinase 1 (ULK1) has been implicated in numerous diseases via regulation of autophagy.…”

The New Face of Autophagy in Chronic Lymphocytic Leukemia

“…On the one hand, the knockout of Ulk1 (a very important autophagy player) in mice helped overcome their resistance to venetoclax and impaired leukemic cell homing, delayed disease progression, and improved the survival of mice with AML [17]. In another type of blood cancer-diffuse large B-cell lymphoma-high-level BECN1 expression is associated with longer survival [18]. Consequently, autophagy does not exert a univocal function as the driver of blood cancers.…”