Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis

Abstract

SummaryIsocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.

Low-Grade Astrocytoma Mutations in IDH1, P53, and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Repression of SOX2

“…Among IDH-mutated LGGs, astrocytomas carry concurrent P53 and chromatin remodeler ATRX loss-of-function mutations, while oligodendrogliomas carry 1p/19q co-deletion and TERT promoter mutations (Cancer Genome Atlas Research et al, 2015). The presence of mutant IDH in two divergent tumor lineages suggests it is a common genetic driver that occurs early in a multipotent progenitor cell (Bardella et al, 2016; Pirozzi et al, 2017; Tirosh et al, 2016; Venteicher et al, 2017). …”

Glioma: experimental models and reality

“…In this model high-grade gliomas develop within weeks after Cre-administration that resemble human glioma with respect to phenotype and BBB [38]. In a recent publication Bardella et al described a transgenic conditional mouse model in which mice carrying a floxed Idh1 minigene, followed by an Idh1 R132H allele were crossed with mice carrying a tamoxifen-inducible P nestin -Cre transgene [7]. Upon administering tamoxifen to the offspring mice, Cre is selectively expressed in nestin-positive neural progenitor cells in the subventricular zone (see also “Human glioma cell lines: neurosphere cultures”), resulting in deletion of the minigene and activation of the Idh1 R132H allele in this alleged stem cell population.…”

“…So far, spontaneous IDH1 mutations have not been reported in murine glioma cell lines, making these models less relevant for the study of IDH mutant human gliomas. Attempts to generate stable cell cultures from transgenic mice, expressing IDH1 R132H in nestin-positive neural progenitor cells have so far also failed [7]. …”

“…No IDH mutations identifiedGenetically heterogeneous, different neural cells may be initiator cellsYesRelevantYesNoGEMMs (conditional expression of oncogenes/loss of tumor suppressor genes)Partly relevant, only few known driver mutations used (among others loss of p53/pten,CDKN2A, kras V12) [38] Existing models expressing IDH1-R132H in neural stem cells have epigenetic alterations but are not tumor models [7]Genetically homogeneous, initiator cell type dependent on promoter driving Cre expression (CMV/nestin/GFAP)YesRelevant when Cre expression is induced in the CNS (intracerebral injection of Cre-lentivirus, crossing mice with developmental CNS- expression of CreYesYesPDX—subcutaneousPartly relevantGenetically homogeneous, but intratumoral heterogeneity due to lack of pre-existent vasculature, development of hypoxia and angiogenesis dependenceNoNon-relevantNoYesPDX—orthotopicRelevantPartly, it is not known to which extent PDX models represent most aggressive parts of the originating tumorNoPartly, only relevant in case PDXs have retained capacity to grow via diffuse infiltrationYesYesCell lines—adherentLess relevantNoNoNon-relevantNoYesCell lines—spheroidsPossibly relevantNoNoNon-relevantNoYesZebrafishNon-relevantNoNoProbably non-relevantNoYesCaninePossibly relevantYesYesRelevantYesNoFruit flyNot relevantNoNoRelevantNoNo …”

Redox-Related Epigenetic Mechanisms in Glioblastoma: Nuclear Factor (Erythroid-Derived 2)-Like 2, Cobalamin, and Dopamine Receptor Subtype 4

“…However, genetic sequencing does not support the hypothesis that mutations are a major causal factor of 5hmC depletion in colorectal, breast, and prostate cancer (72). The expression of mutant IDH1 in the subventricular zone of mice was associated with decreased 5hmeC genomic content and increased 5-methylcytosine levels, mimicking gliomagenesis (73). Therefore, it is plausible that oncometabolite-mediated inhibition of TET activity contributes to the reduced 5hmeC expression observed in these cancers and in glioblastoma.…”