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

Cancer Res. 2020 Dec 1;80(23):5330-5343. doi: 10.1158/0008-5472.CAN-20-2425. Epub 2020 Oct 16.


Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein-Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. SIGNIFICANCE: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5330/F1.large.jpg.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD79 Antigens / genetics
  • Central Nervous System Neoplasms / drug therapy
  • Central Nervous System Neoplasms / metabolism
  • Central Nervous System Neoplasms / mortality
  • Central Nervous System Neoplasms / pathology*
  • Female
  • Glycolysis
  • Hexokinase / genetics
  • Hexokinase / metabolism*
  • Humans
  • Lymphoma / drug therapy
  • Lymphoma / metabolism
  • Lymphoma / mortality
  • Lymphoma / pathology*
  • Mice, SCID
  • Mutation
  • Myeloid Differentiation Factor 88 / genetics
  • NF-kappa B / metabolism
  • NIMA-Interacting Peptidylprolyl Isomerase / metabolism
  • Signal Transduction
  • Transcription Factor RelA / metabolism*
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism
  • Xenograft Model Antitumor Assays


  • CD79 Antigens
  • CD79B protein, human
  • EBV-associated membrane antigen, Epstein-Barr virus
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • NIMA-Interacting Peptidylprolyl Isomerase
  • RELA protein, human
  • Transcription Factor RelA
  • Viral Matrix Proteins
  • HK2 protein, human
  • Hexokinase
  • PIN1 protein, human