Idh1-R132H mutation increases murine hematopoietic progenitors and alters epigenetics.

Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequent in human glioblastomas1 and cytogenetically normal acute myeloid leukemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the “oncometabolite” R-2-hydroxyglutarate (2HG)3. It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukemogenesis. Here we report the characterization of conditional knock-in mice in which the most common IDH1 mutation, Idh1-R132H, is inserted into the endogenous murine Idh1 locus and is expressed in cells of the hematopoietic (Vav-KI) or more specifically in cells of the myeloid (LysM-KI) lineage. These mutants show increased numbers of early hematopoietic progenitors and develop splenomegaly and anemia with extramedullary hematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells exhibit both hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1/2-mutant AML. Thus, our study is the first to describe the generation of conditional Idh1-R132H-KI mice. Furthermore, our study is also the first report showing the induction of a leukemic DNA methylation signature in a modeled system and sheds light on the mechanistic links between IDH1 mutation and human AML. DNA methylation profiling in LSK cells from IDH1-R132H knock-in mice vs. control mice

编码异柠檬酸脱氢酶的IDH1与IDH2基因发生突变，在人类胶质母细胞瘤¹以及细胞遗传学正常的急性髓系白血病（AML）²中十分常见。此类变异属于功能获得性突变，可驱动“癌代谢物”R-2-羟基戊二酸（2HG）³的合成。目前学界尚未明确IDH1与IDH2突变如何调控髓系细胞发育并促进白血病发生。本研究对条件性敲入小鼠开展了特征分析：将最常见的IDH1突变体Idh1-R132H插入内源性小鼠Idh1基因座，使突变基因在造血细胞系（Vav-KI）中表达，或更特异性地在髓系细胞谱系（LysM-KI）中表达。该突变小鼠的早期造血祖细胞数量增多，并出现脾肿大、贫血伴髓外造血现象，提示骨髓微环境功能异常。此外，LysM-KI细胞同时存在组蛋白高甲基化与DNA甲基化改变，该改变与人类IDH1/2突变型AML中观察到的表型一致。因此，本研究首次构建了条件性Idh1-R132H敲入小鼠模型。此外，本研究还首次在模型系统中诱导出白血病相关DNA甲基化特征，并阐明了IDH1突变与人类AML之间的潜在机制关联。IDH1-R132H敲入小鼠与对照小鼠LSK细胞的DNA甲基化谱分析