Identification and overcoming rituximab resistance in diffuse large B-cell lymphoma using next-generation sequencing

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Rituximab, an anti-CD20 monoclonal antibody, is crucial for treating diffuse large B-cell lymphoma (DLBCL).
• Rituximab resistance remains a significant clinical challenge in DLBCL treatment.

Purpose of the Study:

• To investigate the molecular mechanisms underlying rituximab resistance in DLBCL.
• To identify potential therapeutic strategies to overcome rituximab resistance.

Main Methods:

• Developed a rituximab-resistant cell line (RRCL) from a rituximab-sensitive cell line (RSCL).
• Utilized next-generation sequencing to analyze gene expression differences between RSCL and RRCL.
• Investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathway and p38 activation.
• Assessed the efficacy of deferasirox, an NF-κB inhibitor, in combination with rituximab.

Main Results:

• Identified 1,879 differentially expressed genes, with the MAPK signaling pathway showing statistical significance.
• Found increased expression of MAPK13 (encoding p38δ) and elevated phosphop38 levels in RRCL.
• Demonstrated that p38 inhibition reduced phosphop38 expression, suggesting p38 MAPK activation is linked to rituximab resistance.
• Confirmed deferasirox induces dose-dependent cytotoxicity and exhibits synergistic effects with rituximab in RRCL.

Conclusions:

• p38 MAPK activation, particularly p38δ, is associated with rituximab resistance in DLBCL.
• Deferasirox is a potential therapeutic candidate to overcome rituximab resistance, showing synergistic effects when combined with rituximab.