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

• Published in: Cancer research (Chicago, Ill.) Vol. 80; no. 23; pp. 5330 - 5343
• Main Authors: Tateishi, Kensuke, Miyake, Yohei, Kawazu, Masahito, Sasaki, Nobuyoshi, Nakamura, Taishi, Sasame, Jo, Yoshii, Yukie, Ueno, Toshihide, Miyake, Akio, Watanabe, Jun, Matsushita, Yuko, Shiba, Norio, Udaka, Naoko, Ohki, Kentaro, Fink, Alexandria L., Tummala, Shilpa S., Natsumeda, Manabu, Ikegaya, Naoki, Nishi, Mayuko, Ohtake, Makoto, Miyazaki, Ryohei, Suenaga, Jun, Murata, Hidetoshi, Aoki, Ichio, Miller, Julie J., Fujii, Yukihiko, Ryo, Akihide, Yamanaka, Shoji, Mano, Hiroyuki, Cahill, Daniel P., Wakimoto, Hiroaki, Chi, Andrew S., Batchelor, Tracy T., Nagane, Motoo, Ichimura, Koichi, Yamamoto, Tetsuya
• Format: Journal Article
• Language: English
• Published: United States 01.12.2020
• Subjects: 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
• DOI: 10.1158/0008-5472.CAN-20-2425
• ISSN: 0008-5472; 1538-7445

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 and . 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.