Rewired m⁶A epitranscriptomic networks link mutant p53 to neoplastic transformation

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• N6-methyladenosine (m6A) is a key mRNA modification influencing biological and pathological processes.
• The role of m6A epitranscriptomic networks in mutant p53-driven oncogenesis, particularly in Li-Fraumeni syndrome (LFS) gliomas, remains largely unexplored.

Purpose of the Study:

• To investigate how mutant p53 neomorphic functions dysregulate m6A epitranscriptomic networks in LFS-associated neoplastic transformation.
• To elucidate the molecular mechanisms by which mutant p53 drives gliomagenesis in iPSC-derived astrocytes.

Main Methods:

• Utilized iPSC-derived astrocytes from LFS patients with mutant p53.
• Investigated physical interactions between mutant p53, SVIL, and MLL1.
• Assessed the impact of YTHDF2 upregulation on tumor-suppressing transcripts (e.g., CDKN2B, SPOCK2).
• Employed genetic depletion of YTHDF2 and pharmacological inhibition of MLL1 complex.

Main Results:

• Mutant p53, not WT p53, interacts with SVIL to recruit MLL1, activating m6A reader YTHDF2 expression.
• Upregulated YTHDF2 reduces expression of m6A-marked tumor suppressors (CDKN2B, SPOCK2), inducing oncogenic reprogramming.
• Genetic or pharmacological inhibition of YTHDF2/MLL1 significantly impairs mutant p53-driven neoplastic behaviors.

Conclusions:

• Mutant p53 hijacks epigenetic and epitranscriptomic machinery via the p53-SVIL-MLL1-YTHDF2 axis to initiate gliomagenesis.
• This study reveals a novel mechanism of oncogenic reprogramming in LFS gliomas.
• Targeting the YTHDF2/MLL1 pathway presents a potential therapeutic strategy for LFS gliomas.