A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma

Area of Science:

• Oncology
• Neuroscience
• Molecular Biology

Background:

• Primary central nervous system lymphoma (PCNSL) has a poor prognosis despite intensive chemotherapy.
• Genomic studies identified recurrent mutations (MYD88, CD79B) in immunocompetent PCNSL and LMP1 activation in EBV-positive PCNSL.
• Lack of preclinical models hinders understanding of PCNSL pathogenesis.

Purpose of the Study:

• To establish and characterize patient-derived xenograft (PDX) models of PCNSL.
• To elucidate the pathogenic mechanisms driving PCNSL in immunocompetent and EBV-positive cases.
• To identify novel therapeutic targets for PCNSL.

Main Methods:

• Generation of 12 orthotopic PCNSL PDX models from patient biopsies.
• Comprehensive phenotypic, metabolic, and genetic characterization of PDX models.
• Analysis of signaling pathways, including RelA/p65 and hexokinase 2, and their role in tumor growth.

Main Results:

• PDX models faithfully recapitulated PCNSL features, including mutations in MYD88 and CD79B.
• A convergent signaling axis, deregulated RelA/p65-hexokinase 2, was identified in both PCNSL subtypes.
• Inhibition of this axis suppressed PCNSL growth *in vitro* and *in vivo*.

Conclusions:

• Clinically relevant PCNSL xenografts provide a platform for therapeutic discovery.
• The RelA/p65-hexokinase 2 axis is a critical driver of PCNSL progression and a potential therapeutic target.
• Targeting this pathway offers a promising strategy for treating aggressive PCNSL.