Impact of IDH1 mutation on Epitranscriptome regulation in Gliomas

Mutant isocitrate deshydrogenase (IDH) is the key driver mutation of lower
grade gliomas (LGG) and the main determinant for glioma classification.
IDH is a metabolic enzyme which catalyzes the oxidative decarboxylation of
isocitrate to α-ketoglutarate (α-KG). While aberrant DNA methylation has
been widely studied in cancer, the impact of RNA methylation in cancer is
only recently being appreciated. RNA modifications represent an essential
layer of gene expression regulation, leading to the new field of
epitranscriptomics. Only few mRNA modifications have been described,
with N6-methyladenosine (m6A) as the best described so far. Recent
studies have shed light on the importance of m6-A methylation, however
these studies did not consider the role of mutant IDH on the
epitranscriptome regulation in gliomas. Indeed several m6A eraser
enzymatic activities are dependent on α-KG and their function could be
specifically altered in IDH mutated gliomas. Hence, a comprehensive
profiling of m6A RNA methylation and m6A regulators in IDH mutated
gliomas is lacking. Given their complementary expertise, the laboratory of
Dr. Niclou (Luxembourg Institute of Health) and Fuks (Université libre de
Bruxelles) have decided to initiate collaborative efforts to build this
international project. The goal of this project is to determine whether the
expression of the RNA methylation machinery is altered in IDH mutated
gliomas and whether this could lead to changes in m6A RNA methylation
patterns. Our preliminary transcriptomic analysis of glioma patient
specimens indicated that several epitranscriptomic effectors are specifically
deregulated in IDH1 mutated gliomas. In parallel, we will investigate the
functional impact of the m6A writer METTL3 and the m6A reader YTHDC1
on glioma growth and tumorigenic potential in patient-derived xenografts
(PDX). In conclusion, this project will provide new insights on the relevance
of m6A pathway targeting for glioma treatment.