Metabolic control of normal and malignant hematopoiesis

正常和恶性造血的代谢控制

基本信息

批准号：
10033070
负责人：
Andrew Michael Intlekofer
金额：
$ 48.48万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10033070
关键词：
Acute Myelocytic Leukemia Address Affect Biochemical Biological Biology Blood Blood Cells Bone Marrow Cell Differentiation process Cell Lineage Cells Cellular Metabolic Process Chemicals Chromatin Chromatin Remodeling Factor Chromatin Structure Couples Cues Data Enzymes Equilibrium Experimental Models Gene Expression Genes Genetic Genetically Engineered Mouse Growth Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human Hypoxia Hypoxia Inducible Factor In Vitro Isocitrate Dehydrogenase Lactate Dehydrogenase Lead Leukemic Cell Maintenance Malignant - descriptor Malignant Neoplasms Metabolic Metabolic Control Metabolic Pathway Metabolism Molecular Molecular Abnormality Mutation Nature Normal Cell Oncogenic Oxygen Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Population Production Reaction Research Role Signal Transduction Somatic Mutation Source Specimen Stereoisomer System Testing Therapeutic Therapeutic Intervention Tissues Xenograft procedure alpha ketoglutarate cancer cell cancer stem cell cancer therapy chiral molecule chromatin modification delta opioid receptor enantiomer genetic manipulation hematopoietic differentiation in vivo inhibitor/antagonist insight leukemia leukemic stem cell leukemic transformation leukemogenesis mutant new therapeutic target novel novel therapeutic intervention novel therapeutics patient subsets progenitor response self-renewal small molecule inhibitor stem stem cell biology stem cell differentiation stem cell population stem cells stemness targeted treatment therapeutic target tool

项目摘要

PROJECT SUMMARY/ABSTRACT Somatic mutations in the isocitrate dehydrogenase (IDH) enzymes contribute to the pathogenesis of acute myeloid leukemia (AML) and other malignancies via production of the ‘oncometabolite’ D-2-hydroxyglutarate (D-2HG). D-2HG blocks differentiation of malignant cells by inhibiting alpha-ketoglutarate (KG)-dependent enzymes that regulate chromatin structure and gene expression. Small molecule inhibitors of mutant IDH enzymes are promising new therapies for AML, but their efficacy remains limited to the subset of patients with IDH mutations. This raises the question as to whether analogous metabolic aberrations might contribute to leukemogenesis in IDH-wildtype AML. Intriguingly, 2HG is a chiral molecule that can exist in either the D- or L- enantiomer. Although cancer-associated IDH mutants exclusively produce D-2HG, biochemical studies indicate that L-2HG can function as a ~10-fold more potent inhibitor of many KG-dependent enzymes, including chromatin modifiers and regulators of hypoxia-inducible factor (HIF) stability. However, biological sources and activities of L-2HG have been poorly understood. We identified a metabolic pathway wherein normal and malignant cells without IDH mutations selectively produce L-2HG in response to oxygen limitation (a.k.a. hypoxia) through an unusual reaction catalyzed by lactate dehydrogenase (LDHA). We show that hypoxia-induced L-2HG enhances stability of HIF, increases repressive chromatin modifications, and blocks differentiation of stem/progenitor cells. These findings suggest that L-2HG might account, at least in part, for the importance of hypoxic niches, HIF, and LDHA in balancing self-renewal and differentiation of stem cell populations, including hematopoietic stem/progenitor cells (HSPC) and leukemia stem cells. Thus, we hypothesize that L-2HG functions as a metabolic signal that couples hypoxic niches to the maintenance of normal blood stem cells and leukemia stem cells. This hypothesis will be rigorously addressed in three Specific Aims. Aim 1 will define the molecular mechanisms by which L-2HG regulates blood cell differentiation in vitro. In this Aim, we will define the effects of L-2HG on gene expression and chromatin structure and determine how these inputs balance HSPC stemness and lineage differentiation. Aim 2 will determine how L-2HG functions to control normal and malignant hematopoiesis in vivo. This Aim will use novel genetically engineered mouse models that allow for tissue-specific, inducible manipulation of L-2HG levels in order to dissect the role of L-2HG in normal hematopoiesis and leukemia. Aim 3 will elucidate the oncogenic mechanisms and therapeutic potential of L-2HG in human leukemia. In this Aim, we will use primary AML biospecimens and patient-derived xenografts to determine the mechanisms that lead to deregulated L- 2HG in a subset of AML and assess whether depleting L-2HG offers a promising strategy to treat human AML. The proposed studies will offer fundamental insights into the metabolic control of normal and malignant stem cell biology and expand the applicability of metabolic targeted therapies for leukemia and other cancers.

项目概要/摘要异柠檬酸脱氢酶 (IDH) 的体细胞突变导致急性白血病的发病机制通过产生“致癌代谢物”D-2-羟基戊二酸来治疗骨髓性白血病 (AML) 和其他恶性肿瘤 (D-2HG)。D-2HG 通过抑制 α-酮戊二酸 (αKG) 依赖性来阻断恶性细胞的分化。调节染色质结构和基因表达的酶，突变 IDH 的小分子抑制剂。酶是治疗 AML 的有前途的新疗法，但其疗效仍然仅限于患有 AML 的患者亚群这提出了类似的代谢异常是否可能导致的问题。 IDH 野生型 AML 中的白血病发生有趣的是，2HG 是一种手性分子，可以存在于 D- 或 L- 中。尽管与癌症相关的 IDH 突变体只产生 D-2HG，但生化研究表明 L-2HG 可以作为许多 αKG 依赖性酶的约 10 倍有效的抑制剂，包括染色质修饰剂和缺氧诱导因子 (HIF) 稳定性调节剂。我们对 L-2HG 的来源和活性知之甚少。没有 IDH 突变的正常和恶性细胞选择性地产生 L-2HG 以响应氧限制（又名缺氧）通过乳酸脱氢酶（LDHA）催化的不寻常反应。缺氧诱导的 L-2HG 增强 HIF 的稳定性，增加抑制性染色质修饰，并阻断这些发现表明，L-2HG 可能至少部分地解释了干细胞/祖细胞的分化。缺氧生态位、HIF 和 LDHA 在平衡干细胞自我更新和分化中的重要性群体，包括造血干/祖细胞（HSPC）和白血病干细胞。研究发现，L-2HG 作为一种代谢信号，将缺氧生态位与维持正常血液干细胞和白血病干细胞的这一假设将得到严格的验证。三个具体目标中提到的目标 1 将定义 L-2HG 调节的分子机制。在这个目标中，我们将定义 L-2HG 对基因表达和血细胞分化的影响。染色质结构并确定这些输入如何平衡 HSPC 干性和谱系分化。 2 将确定 L-2HG 如何发挥作用来控制体内正常和恶性造血。新型基因工程小鼠模型，可对 L-2HG 进行组织特异性诱导操作目的 3 将阐明 L-2HG 在正常造血和白血病中的作用。 L-2HG 在人类白血病中的致癌机制和治疗潜力在这一目标中，我们将使用初级药物。 AML 生物样本和患者来源的异种移植物，以确定导致 L- 失调的机制 2HG 在 AML 的一个子集中，并评估消耗 L-2HG 是否为治疗人类 AML 提供了一种有前景的策略。拟议的研究将为正常和恶性干细胞的代谢控制提供基本见解细胞生物学并扩大代谢靶向治疗对白血病和其他癌症的适用性。