Metabolic pathways in leukemia

白血病的代谢途径

基本信息

批准号：
8864420
负责人：
JOHN D SCHUETZ
金额：
$ 40.72万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8864420
关键词：
ABCG2 gene ATP-Binding Cassette Transporters Accounting Acute Megakaryocytic Leukemias Acute Myelocytic Leukemia Adult Adult Acute Myeloblastic Leukemia Affect Apoptosis Apoptotic BCL2 gene Biochemical Blast Cell Cell Death Cell membrane Cells Chemicals Child Childhood Childhood Acute Myeloid Leukemia Data Development Disease Drug Transport Ensure Gene Expression Profile Genetic Genetic Models Glutathione Heme Homeostasis Human In Vitro Investigation Knock-out Knowledge Location MYCN gene Mediating Metabolic Metabolic Pathway Metabolism Microarray Analysis Mitochondria Modeling Mus Myelogenous Myeloid Leukemia Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacogenetics Porphyrins Regulation Stem cells Superoxides Survival Rate Techniques Testing Therapeutic base high throughput screening improved in vivo in vivo Model inhibitor/antagonist killings leukemia leukemogenesis novel novel therapeutics porphyrin a porphyrin biosynthesis porphyrin metabolism pre-clinical progenitor protoporphyrin IX public health relevance response self-renewal sound therapeutic target transport inhibitor

项目摘要

DESCRIPTION (provided by applicant): The prospects for long-term survival of patients, both adults and children, with acute myeloid leukemia (AML) are poor. The response to therapy is often variable and many studies are focusing on pharmacogenetic differences in metabolism and transport of drugs to account for poor response. A complementary approach in AML is to identify key metabolism and transporter differences and then target these potential points of vulnerability with drugs to improve therapeutic outcome. In both pediatric and adult AML, MYCN is frequently upregulated. Among AML patients with increased MYCN expression, a porphyrin transporter (ABCG2) is upregulated along with the heme/porphyrin metabolic pathway. There is no treatment in MYCN- driven AML that is directed towards these metabolic changes. Our promising preliminary data show that survival of MYCN-driven leukemic progenitors is negatively impacted when porphyrin metabolism is disrupted by either chemical inhibition or deletion of the ABC transporter, ABCG2. This indicates that porphyrin export by ABCG2 is required for self-renewal of leukemic progenitors. We propose three sets of highly integrated studies that will test our central hypothesis that ABCG2 transporter mediated regulation of porphyrin metabolism is crucial for survival of MYCN-driven leukemic progenitors and blasts. (1) Using in vitro and in vivo AML models, we will investigate the relationship between porphyrin metabolism, ABCG2 expression and function, and leukemic progenitor survival. (2) Using high- throughput screening, we will identify novel inhibitors of ABCG2 that impact both catalytic activity and subcellular location. (3) Elucidate how excess porphyrins produce cell death focusing on pathways that involve the glutathione pathway as well as anti-apoptotic pathways. These studies of the porphyrin transporter, ABCG2, in the context of MYCN-driven AML, provide a unique opportunity to develop new knowledge and improve therapy.

描述（由适用提供）：患者（成人和儿童）长期生存的前景，急性骨髓性白血病（AML）很差。对治疗的反应通常是可变的，许多研究重点是代谢和药物运输的药物遗传学差异，以说明反应不佳。 AML中的一种完整方法是确定关键的新陈代谢和转运蛋白差异，然后用药物来针对这些脆弱性，以改善治疗结果。在小儿和成人AML中，MYCN经常更新。在MYCN表达增加的AML患者中，卟啉转运蛋白（ABCG2）与血红素/卟啉代谢途径一起更新。在MyCN驱动的AML中没有针对这些代谢变化的治疗方法。我们承诺的初步数据表明，当卟啉代谢因化学抑制或ABC转运蛋白ABCG2的化学抑制或缺失而丧失卟啉代谢时，霉菌驱动的白血病祖细胞的存活受到负面影响。这表明白血病祖细胞自我更新需要ABCG2的卟啉导出。我们提出了三组高度综合的研究，这些研究将检验我们的中心假设，即ABCG2转运蛋白介导的卟啉代谢的调节对于MYCN驱动的白血病祖细胞和爆炸的存活至关重要。（1）使用体外和体内AML模型，我们将研究卟啉代谢，ABCG2表达和功能与白血病祖细胞存活之间的关系。（2）使用高通量筛选，我们将确定影响催化活性和亚细胞位置的新型ABCG2抑制剂。（3）阐明如何超越卟啉会产生细胞死亡，重点是包括谷胱甘肽途径以及抗凋亡途径。在MYCN驱动的AML的背景下，对卟啉转运蛋白转运蛋白ABCG2的这些研究为发展新知识和改善治疗提供了独特的机会。