Data from A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma
Rattachement africain : jp, us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Abstract 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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Data from A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma
- Date Crossref
- 31/03/2023
- Éditeur
- American Association for Cancer Research (AACR)
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Yokohama City University Neurosurgical-Oncology Laboratory pays non établi dans la noticeUniversité ou école supérieure
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Kyorin University Department of Neurosurgery pays non établi dans la noticeUniversité ou école supérieure
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National Institutes for Quantum Science and Technology pays non établi dans la noticeStructure de recherche
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Yokohama City University Hospital pays non établi dans la noticeÉtablissement de santé
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Niigata University Department of Neurosurgery pays non établi dans la noticeUniversité ou école supérieure
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National Center For Child Health and Development pays non établi dans la noticeOrganisme public
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Massachusetts General Hospital Department of Neurosurgery pays non établi dans la noticeÉtablissement de santé
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Center for Neuro-Oncology pays non établi dans la noticeStructure de recherche
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Mirati Therapeutics (United States) pays non établi dans la noticeEntreprise
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Brigham and Women's Hospital Department of Neurology pays non établi dans la noticeÉtablissement de santé
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Harvard University pays non établi dans la noticeUniversité ou école supérieure
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Graduate School of Medicine Department of Neurosurgery pays non établi dans la noticeUniversité ou école supérieure
Neurosurgical-Oncology Laboratory — Yokohama City University, Department of Neurosurgery — Kyorin University et National Institutes for Quantum Science and Technology, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.