Role of IDH Mutations in Acute Myeloid Malignancies

描述（由申请人提供）：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 突变如何促进白血病细胞增殖和存活方面已经取得了进展，但对于细胞分化能力如何受到抑制的情况知之甚少。最近关于这个问题的大多数研究都描绘了癌基因在维持干细胞表型所需基因表达中的作用，其中许多无疑与 AML 发病机制有关。异柠檬酸脱氢酶 1 (IDH1) 和异柠檬酸脱氢酶 2 (IDH2) 中反复发生的突变会导致产生代谢物 2-羟基戊二酸 (2HG) 的功能获得性，这一发现提示了一种可以阻止正常分化的额外机制。我们发现 2HG 可以作为 DNA 羟化酶 TET 家族和组蛋白去甲基化酶 Jumonji 家族的竞争性抑制剂。因此，IDH 突变细胞表现出增强的 DNA 和组蛋白甲基化。这种增强的甲基化与白血病细胞无法激活参与细胞分化的谱系特异性基因相关。尽管存在这些相关性，IDH1 和 IDH2 突变对白血病的预后影响仍然存在差异，而且 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 3 个具体目标： 1) 研究 IDH1 R132 或 IDH2 R172 与 IDH2 R140 突变对白血病预后的差异影响的机制基础； 2）比较IDH突变与TET2突变对AML组蛋白甲基化状态和基因表达的影响； 3) 确定控制 2HG 水平是否可以抑制 IDH 相关白血病。通过我们提出的研究，我们希望扩大我们对造血分化分子调控的理解，为 AML 病例中观察到的染色质结构差异提供解释，并开发新的 AML 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.