Genetic modeling of ELP1-associated Sonic hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target.
Zusammenfassung: Germline loss-of-function (LOF) variants in Elongator acetyltransferase complex subunit 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ∼30% of the Sonic hedgehog (SHH) 3 subtype. The mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous Elp1 LOF (Elp1) seen in affected germline carriers exhibit hallmark features of premalignancy in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1 GNPs harboring somatic Ptch1 inactivation yields SHH-MB-like tumors with compromised p53 signaling, providing a plausible explanation for the exclusivity of ELP1-associated MBs in the SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivates p53-dependent apoptosis and extends survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics targeting MDM2 as a rational treatment option.
Autoren: Shiekh Tanveer Ahmad, Yiran Li, Jesus Garcia-Lopez, Brian L Gudenas, Jennifer Hadley, Leena Paul, Stephanie C Wu, Alaa Refaat, Marija Kojic, Melissa Batts, Taha Soliman, Aaron Pitre, Frederik Arnskötter, Frederique Zindy, Alun Jones, Nathaniel R Twarog, Anand Mayasundari, Brandon Bianski, Christopher Tinkle, Abbas Shirinifard, Laura Janke, Meifen Lu, Sara A Lewis, Arzu Onar-Thomas, Stefan M Pfister, Amar Gajjar, Suzanne J Baker, Martine F Roussel, Zoran Rankovic, Giles W Robinson, Brent A Orr, Brandon Wainwright, Anang A Shelat, Sebastian M Waszak, Lena M Kutscher, Hong Lin, Paul A Northcott
Veröffentlicht: Jun 2025 / Journal: Cancer cell
AhR activation mitigates graft-versus-host disease of the central nervous system by reducing microglial NF-κB signaling.
Zusammenfassung: Acute graft-versus-host disease (GVHD) that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) can affect the central nervous system (CNS). Most patients who have undergone allo-HCT receive antibiotic treatment, which alters the microbiome and essential microbiome-derived metabolites. We investigated the impact of microbiome modifications on CNS GVHD and therapeutic strategies to overcome the microbiome-derived metabolite depletion. Antibiotic treatment of mice undergoing allo-HCT increased microglia numbers in the brain, indicating increased inflammation. In addition, microglial morphology shifted toward a highly branched phenotype. Consistent with a proinflammatory phenotype, the microglia exhibited increased NF-κB and Src activity. Antibiotic treatment caused the depletion of the bacteria-derived aryl hydrocarbon receptor (AhR) ligand indole-3-acetate in the brain. Conversely, treatment of the primary microglia with the AhR ligand 6-formylindolo(3,2-b)carbazole (FICZ) reduced NF-κB activity and phagocytic potential. Microglia expansion and morphological changes were reversed by AhR ligand FICZ treatment. Moreover, the AhR ligand indole-3-acetate was also reduced in the CNS of patients who developed acute GVHD concomitant with increased microglial NF-κB expression. In summary, we demonstrated that antibiotic treatment and a subsequent decrease of AhR ligands resulted in increased microglial activation in CNS GVHD. FICZ treatment hampered CNS inflammation by inhibiting NF-κB activity, thereby providing a metabolic modifier to interfere with pathogenic microglia signaling and CNS GVHD in vivo.
Autoren: Alexander Zähringer, Inês Morgado, Daniel Erny, Florian Ingelfinger, Jana Gawron, Sangya Chatterjee, Valentin Wenger, Dominik Schmidt, Lennard Schwöbel, Rachael C Adams, Marlene Langenbach, Alina Hartmann, Natascha Osswald, Julian Wolf, Günther Schlunck, Priscilla S Briquez, Kathleen Grueter, Dietrich A Ruess, Ian Frew, Ann-Cathrin Burk, Verena Holzmüller, Bodo Grimbacher, David Michonneau, Geoffroy Andrieux, Gérard Socié, Julia Kolter, Melanie Boerries, Marie Follo, Franziska Blaeschke, Lisa Sevenich, Marco Prinz, Robert Zeiser, Janaki Manoja Vinnakota
Veröffentlicht: Jun 2025 / Journal: Blood advances