Genetic modeling of ELP1-associated Sonic hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target.

in Cancer cell by 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

TLDR

  • ELP1 deficiency provokes SHH-MB pathogenesis through mechanisms involving DNA replication stress, genomic instability, and p53 compromise.

Abstract

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 Elp1GNPs 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.

Overview

  • The study investigated the role of germline loss-of-function (LOF) variants in Elongator acetyltransferase complex subunit 1 (ELP1) in childhood medulloblastoma (MB) predisposition.
  • The study used genetically engineered mice to model ELP1 deficiency and observed hallmark features of premalignancy in cerebellar granule neuron progenitors (GNPs) such as increased DNA replication stress, genomic instability, and accelerated cell cycle.
  • The primary objective of the study was to elucidate the molecular mechanisms underlying ELP1-associated MB pathogenesis and identify potential therapeutic targets.

Comparative Analysis & Findings

  • Genetically engineered mice modeling ELP1 deficiency exhibited hallmark features of premalignancy in GNPs, which were associated with increased DNA replication stress, genomic instability, and accelerated cell cycle.
  • Orthotopic transplantation of Elp1GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling.
  • Treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivated p53-dependent apoptosis and extended survival.

Implications and Future Directions

  • The study functionally substantiates the role of ELP1 deficiency in SHH-MB predisposition and identifies MDM2 inhibitors as a potential therapeutic option.
  • Future studies should investigate the mechanisms by which ELP1 deficiency leads to p53 compromise and explore the potential benefits of MDM2 inhibition in ELP1-associated MB patients.
  • Additional research is needed to determine the optimal dosing and administration schedule of MDM2 inhibitors in ELP1-associated MB patients.
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