Biomarker potential of nuclear Nrf2 activation in the ABC subtype of diffuse large B‑cell lymphoma

Oncol Lett. 2024 Oct 25;29(1):30. doi: 10.3892/ol.2024.14776. eCollection 2025 Jan.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma characterized by distinct subtypes and heterogeneous treatment outcomes. Oxidative stress and the dysregulation of related regulatory genes are prevalent in DLBCL, prompting an investigation into the nuclear factor erythroid 2-related factor 2 (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) signaling pathway and associated genes. The present study assessed pathological specimens and clinical data from 43 newly diagnosed patients with DLBCL, comparing the associations and correlations between the expression of Nrf2, Keap1, microtubule-associated protein 1 light chain 3β (LC3B) and nitrotyrosine and the activated B-cell (ABC) and germinal center B-cell (GCB) subtypes of DLBCL using immunohistochemistry and digital image analysis software. Nuclear Nrf2 activation was observed in 33.3% of patients with DLBCL ABC, demonstrating a higher prevalence of hepatitis B surface antigen positivity, calcium ions and significant body weight loss (P<0.05). Total Nrf2 expression was associated with the DLBCL GCB subtype and inversely correlated with Keap1 expression in the DLBCL ABC subtype. Furthermore, a positive correlation was demonstrated between Nrf2 and LC3, indicating that total Nrf2 is inhibited by Keap1 and regulates LC3 expression. The ABC subtype was also associated with lower white blood cell counts and more frequent chemotherapy courses than the GCB subtype. These findings suggest that nuclear Nrf2 could be a biomarker for DLBCL clinical diagnosis.

Keywords: activated B-cell; diffuse large B-cell lymphoma; germinal center B-cell; kelch-like ECH-associated protein 1; microtubule-associated protein 1 light chain 3β; nitrotyrosine; nuclear factor erythroid 2-related factor 2.

Grants and funding

The present study was supported by the Kaohsiung Medical University Hospital [grant nos. KMUH109-M907, KMUH111-1R16, KMUH111-1M17, KMUH112-2M12, KMUH112-2M13 and KMUH-DK(B)111002-3] and the Ministry of Health and Welfare (grant no. MOHW112-TDU-B-212-144006).