Abstract
IDH1 mutation leads to increased hematopoietic progenitors and DNA hypermethylation in vivo.
Major finding: IDH1 mutation leads to increased hematopoietic progenitors and DNA hypermethylation in vivo.
Approach: The IDH1R132H mutant was conditionally expressed in hematopoietic cells or the myeloid lineage.
Impact: This knock-in mouse model provides insight into the role of IDH1 mutations in leukemogenesis.
Gain-of-function mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are commonly found in glioblastomas and acute myeloid leukemia (AML). These mutations are believed to lead to widespread epigenetic alterations through the abnormal accumulation of the metabolite R-2-hydroxyglutarate (2HG), which competitively inhibits enzymes that regulate DNA and histone demethylation, but it is unclear how this might promote oncogenesis. Sasaki and colleagues generated conditional knock-in mouse models in which the most common IDH1 mutation, IDH1R132H, was expressed in all hematopoietic cells or specifically in the myeloid lineage. Both types of mice were viable and fertile, and young mice had normal peripheral blood, indicating that hematopoietic development was not significantly affected by IDH1 mutation. However, expression of mutant IDH1 in the myeloid lineage led to mild splenic enlargement in young mice that progressed to splenomegaly with disorganization of splenic architecture and extramedullary hematopoiesis. IDH1-mutant mice also showed an age-dependent expansion in hematopoietic stem cell (HSC) and lineage-restricted progenitor populations that was associated with increased cell division and proliferation. Elevated serum 2HG levels in the mutant mice were accompanied by significant changes in gene expression and global increases in DNA and histone methylation. Notably, the set of hypermethylated mouse genes in the myeloid-lineage IDH1R132H mutants significantly overlapped with the set of human genes that are hypermethylated in IDH1/IDH2–mutant AMLs, demonstrating that expression of IDH1R132H induces a leukemic DNA methylation signature. These findings thus establish that IDH1 mutation leads to inappropriate expansion of immature progenitor cells and provide a tool for studying the effects of IDH1-induced epigenetic changes.
