Project Summary/Abstract
Gliomas are incurable and are among the most fatal tumors in adult. Monoallelic mutations of IDH1 and
IDH2, which encode isocitrate dehydrogenases (IDH) that convert isocitrate into a-ketoglutarate (aKG), have
been detected in nearly all secondary glioblastoma multiforme (GBM) and in 80% of low grade (WHO grade II)
gliomas (LGGs). However, because IDH mutation-bearing glioma cells are difficult to isolate and propagate, an
experimental system that allows dissection of the roles of IDH mutations and the subsequent genetic events in
gliomagenesis is currently unavailable. Our overall goal is to understand the molecular mechanism underlying
gliomagenesis and to identify novel targets to treat gliomas. It is generally believed that gliomas are originated
from brain progenitor cells such as neural progenitor cells (NPCs). However, these cells are inaccessible for
experimentation. Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and
induced pluripotent stem cells (iPSCs), have the potential to differentiate into every somatic cell types. Therefore,
we hypothesize that hPSCs serve as an alternative source for human brain progenitor cells, which can be used
to dissect the roles of IDH mutations and other associated genetic events in LGGs. The objective of this proposal
is to establish a novel stem cell model for LGGs, which will allow assessing the roles of IDH1 mutations and
other glioma-associated genetic alterations in disease-relevant cell types. The rationale is that by establishing
such a LGG model, we will be able to dissect the underlying molecular mechanism of gliomagenesis. These
discoveries will ultimately facilitate identification of novel therapeutic targets and strengthen our capacity for
therapeutic intervention. To achieve the objective, two specific aims are proposed. In Aim 1, we will genetically
engineer normal hPSCs to enable conditional expression of the mutant IDH1 in disease-relevant cell types. In
Aim 2, we will reprogram IDH mutation-bearing primary LGG cells into iPSC and assess cellular and molecular
features of the LGG-iPSC-derived NPCs in a brain organoid model. If successfully completed, we expect to
establish a novel stem cell model for LGGs, which will enable us to assess the specific roles of IDH mutations
and other glioma-associated early genetic alterations. The project will ultimately facilitate identification of novel
drug targets and development of new therapies to treat gliomas.