Metabolic pathways in leukemia

白血病的代谢途径

基本信息

批准号：
9015750
负责人：
JOHN D SCHUETZ
金额：
$ 40.97万
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/9015750
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 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 mouse model novel novel therapeutic intervention porphyrin a porphyrin biosynthesis porphyrin metabolism pre-clinical progenitor protoporphyrin IX public health relevance response self-renewal sound therapeutic target therapy outcome 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（由申请人提供）：急性髓系白血病 (AML) 患者（无论是成人还是儿童）的长期生存前景较差。对治疗的反应通常是可变的，许多研究都集中在代谢和药物遗传学方面的差异。解决 AML 反应不佳的一种补充方法是确定关键的代谢和转运蛋白差异，然后用药物瞄准这些潜在的脆弱点，以改善治疗结果。在儿童和成人 AML 中，MYCN 经常上调。 MYCN 表达增加的 AML 患者，卟啉转运蛋白 (ABCG2) 与血红素/卟啉代谢途径一起上调。目前尚无针对 MYCN 驱动的 AML 的治疗方法，我们有希望的初步数据表明 MYCN 的存活。当 ABC 转运蛋白 ABCG2 的化学抑制或删除破坏卟啉代谢时，驱动的白血病祖细胞会受到负面影响。这表明 ABCG2 的卟啉输出受到影响。我们提出了三组高度综合的研究，以检验我们的中心假设，即 ABCG2 转运蛋白介导的卟啉代谢调节对于 MYCN 驱动的白血病祖细胞和原始细胞的存活至关重要 (1) 使用体外。和体内 AML 模型，我们将研究卟啉代谢、ABCG2 表达和功能以及白血病祖细胞存活之间的关系 (2) 使用高通量筛选，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。确定影响催化活性和亚细胞定位的新型 ABCG2 抑制剂。 (3) 阐明过量卟啉如何导致细胞死亡，重点关注涉及谷胱甘肽途径以及抗凋亡途径的这些研究。 MYCN 驱动的 AML 的背景提供了开发新知识和改进治疗的独特机会。