Diffuse large B-cell lymphoma (DLBCL) patients with 17p deletion (17p^-) show variable outcomes under R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy. ALOX15B (arachidonate 15-lipoxygenase type B), located on chromosome 17p, regulates immune responses via arachidonic acid (AA) metabolism. This study investigates its role in DLBCL progression and explores its epigenetic regulation and therapeutic potential.

We analyzed bulk and single-cell transcriptomic data from DLBCL cohorts to evaluate ALOX15B expression and its correlation with clinical outcomes, immune microenvironment, and therapy resistance. Functional assays using siRNA knockdown, luciferase reporter, and drug sensitivity experiments were performed in DLBCL cell lines. Murine and patient-derived xenograft (PDX) models were employed to assess tumor behavior and treatment efficacy in vivo. Chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), were conducted to explore the epigenetic regulation of ALOX15B.

Low ALOX15B expression was associated with inferior progression-free survival (PFS), immunosuppressive microenvironment, and reduced CD8 ⁺ T cell cytotoxicity in DLBCL. Mechanistically, ALOX15B deficiency led to upregulation of COX-2/PGE2 signaling and downregulation of the TAP1/MHC-I antigen presentation axis. Silencing ALOX15B promoted tumor cell proliferation and resistance to doxorubicin. Epigenetically, HDAC1/2 were enriched at the ALOX15B promoter region, repressing its expression. Treatment with the HDAC inhibitor tucidinostat restored ALOX15B expression, enhanced tumor cell apoptosis, reinstated antigen presentation, and reprogrammed the tumor immune landscape in both cell lines and in vivo models.

ALOX15B is a key epigenetically regulated gene in DLBCL that modulates the tumor immune microenvironment and response to chemotherapy. Its downregulation promotes immune evasion and treatment resistance, while tucidinostat effectively restores its expression and anti-tumor immunity. These findings highlight ALOX15B as a prognostic biomarker and therapeutic target, particularly in 17p⁻ DLBCL.