Role of IDH Mutations in Acute Myeloid Malignancies

IDH 突变在急性髓系恶性肿瘤中的作用

• 批准号: 8503916
• 负责人: CRAIG B THOMPSON
• 金额: $ 36.69万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503916
• 关键词: Acetylation; Acute; Acute Myelocytic Leukemia; Address; Adult Acute Myeloblastic Leukemia; Affect; Cell Differentiation process; Cells; Chromatin; Chromatin Structure; Code; DNA; DNA Methylation; Data; Enzymes; Epigenetic Process; FLT3 gene; Family; Gene Expression; Genes; Genetic; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Heterochromatin; Histones; Hydroxylation; In Vitro; Isocitrate Dehydrogenase; Leukemic Cell; Link; Lysine; Methylation; Mixed Function Oxygenases; Modification; Molecular; Mutation; Myeloproliferative disease; Neoplastic Cell Transformation; Oncogenes; Pathogenesis; Patients; Pattern; Phenotype; Play; Population; Production; Property; Proteins; RNA Interference; Recurrence; Regulation; Reporting; Research; Role; Sampling; Stem cells; Testing; Transplantation; Uncertainty; Work; base; cancer cell; chromatin remodeling; demethylation; gain of function; inhibitor/antagonist; leukemia; leukemogenesis; loss of function; loss of function mutation; mutant; novel therapeutic intervention; outcome forecast; prevent; progenitor; prognostic; public health relevance; reconstitution; research study

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.

描述（由申请人提供）：急性髓细胞性白血病（AML）的标志是恶性细胞分化的能力的深刻障碍。尽管在理解AML突变如何促进白血病细胞的增殖和存活方面取得了进展，但对细胞如何抑制细胞分化的能力的了解相对较少。关于此问题的大多数研究都描述了癌基因在维持维持干细胞表型所需的基因表达中的作用，其中许多无疑都导致了AML发病机理。在异位酸脱氢酶1（IDH1）和异位酸脱氢酶2（IDH2）中发现复发突变，从而导致功能获得的能力产生代谢物2-羟基耐糊状（2HG）的能力，提出了正常差异的附加机制。我们发现2HG可以充当DNA羟化酶TET家族和组蛋白脱甲基酶的Jumonji家族的竞争性抑制剂。结果，IDH突变细胞显示出增强的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涉及细胞分化的谱系特异性基因相关。尽管存在这些相关性，但在白血病中IDH1和IDH2突变的预后含义以及关于2HG在其转化特性中所起的作用的不确定性仍然存在差异。为了解决这些问题，我们提出了3个具体目的：1）研究白血病预后中IDH1 R132或IDH2 R172与IDH2 R140突变的机械基础； 2）比较IDH突变与TET2突变对AML中组蛋白甲基化状态和基因表达的影响； 3）确定2HG水平的操纵是否可以抑制与IDH相关的白血病。通过我们提出的研究，我们希望扩大对造血分化的分子调节的理解，为在AML病例中观察到的染色质结构的差异提供了解释，并开发了新的AML治疗方法。