Role of IDH Mutations in Acute Myeloid Malignancies

描述(申请人提供)：急性髓系白血病(AML)的特点是恶性细胞分化能力严重受阻。尽管在了解AML突变如何有助于增加白血病细胞的增殖和存活方面取得了进展，但对细胞分化能力如何受到抑制的了解相对较少。最近关于这一问题的大多数研究都描绘了癌基因在维持维持干细胞表型所需基因表达方面的作用，其中许多无疑参与了AML的发病机制。异柠檬酸脱氢酶1(IDH1)和异柠檬酸脱氢酶2(IDH2)的反复突变导致产生代谢产物2-羟基戊二酸(2HG)的功能增强，这表明可以阻止正常分化的另一种机制。我们发现2HG可以作为DNA羟基酶Tet家族和组蛋白去甲基酶Jumonji家族的竞争性抑制物。因此，IDH突变细胞显示出增强的DNA和组蛋白甲基化。这种甲基化增强与白血病细胞无法激活涉及细胞分化的谱系特异性基因有关。尽管存在这些相关性，但在白血病中IDH1和IDH2突变的预后意义上仍存在差异，2HG在其转化特性中所起的作用也存在不确定性。为了解决这些问题，我们提出了三个具体目标：1)研究IDH1 R132或IDH2 R172和IDH2 R140突变在白血病预后中的不同意义的机制基础；2)比较IDH突变和TET2突变对AML组蛋白甲基化状态和基因表达的影响；3)确定操纵2HG水平是否可以抑制IDH相关白血病。通过我们提出的研究，我们希望拓宽我们对造血分化分子调控的理解，为观察到的AML病例之间染色质结构的差异提供解释，并开发AML的新治疗方法。

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is marked by a profound block in the ability of the malignant cells to differentiate. Although progress has been made in understanding how the mutations in AML contribute to increasing the proliferation and survival of the leukemic cells, relatively little is known about how the cells' ability to differeniate is inhibited. Most of the recent research on this issue has delineated a role for oncogenes in maintaining the expression of genes required to maintain a stem cell phenotype and many of these undoubtedly contribute to AML pathogenesis. The discovery of recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) that result in a gain-of-function ability to produce the metabolite 2-hydroxyglutarate (2HG) has suggested an additional mechanism by which normal differentiation can be blocked. We have found that 2HG can act as a competitive inhibitor of both the TET family of DNA hydroxylases and the Jumonji family of histone demethylases. As a consequence, IDH-mutant cells display enhanced DNA and histone methylation. This enhanced methylation correlated with the inability of leukemic cells to activate lineage-specific genes involved in cellular differentiation. Despite these correlations, there remain differences in the prognostic implications of IDH1 and IDH2 mutations in leukemia and uncertainty concerning the role 2HG plays in their transforming properties. To address these issues we propose 3 Specific Aims: 1) Investigate the mechanistic basis for the differential implication of IDH1 R132 or IDH2 R172 versus IDH2 R140 mutations in leukemic prognosis; 2) Compare the effects of IDH mutation versus TET2 mutation on histone methylation status and gene expression in AML; 3) Determine if the manipulation of 2HG levels can suppress IDH-associated leukemia. Through our proposed studies we hope to broaden our understanding of the molecular regulation of hematopoietic differentiation, provide an explanation for the differences in the chromatin structure observed among AML cases, and develop new therapeutic approaches to AML.