Cause and therapeutic impact of DNA-protein crosslink repair defect in myeloid leukemias

髓系白血病 DNA-蛋白质交联修复缺陷的原因和治疗影响

基本信息

批准号：
10296087
负责人：
SCOTT H KAUFMANN
金额：
$ 36.37万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10296087
关键词：
AML/MDS Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Affect Age Anthracycline Antibodies Azacitidine Biochemical Camptothecin Cancer Therapy Evaluation Program Case Fatality Rates Cell Line Cells Chronic Myelomonocytic Leukemia Clinic Clinical Complex Cytotoxic agent DNA DNA Damage DNA Methyltransferase Inhibitor DNA Modification Methylases DNA Topoisomerases DNA lesion DNA-protein crosslink Daunorubicin Decitabine Defect Development Disease Drug usage Enzymes Etoposide Excision Exhibits Exposure to Formaldehyde Generations Hematopoietic Hematopoietic Stem Cell Transplantation Hemorrhagic Thrombocythemia Human Immunologics In Vitro Knock-out Lead Lesion Leukemic Cell Lymphoid Cell Malignant - descriptor Marrow Measures Metabolism Metalloproteases Mitoxantrone Myeloid Cells Myeloid Leukemia Myeloproliferative disease Neoplasms Nuclear Participant Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacotherapy Phase Play Poison Polycythemia Vera Process Reagent Regimen Role Sampling Serine Protease Specimen Stabilizing Agents Syndrome TOP1 gene TOP2A gene Testing Therapeutic Tissues Topoisomerase Topotecan acute myeloid leukemia cell antileukemic agent base cell type chromatin protein comorbidity covalent bond crosslink design drug sensitivity high reward high risk histone demethylase improved improved outcome in vivo in vivo Model insight leukemia nuclease phase II trial phosphoric diester hydrolase progenitor repaired research clinical testing response targeted agent targeted treatment

项目摘要

ABSTRACT Acute myeloid leukemias (AMLs) are a genetically heterogeneous group of clonal hematopoietic disorders characterized by accumulation of immature non-lymphoid marrow progenitors. While there have been notable therapeutic advances over the past 5 years, many AML subtypes continue to have case fatality rates of >50%. Despite the introduction of a number of targeted therapies, conventional cytotoxic drugs – alone or in combination with the targeted agents – remain the mainstay of AML therapy. Among the conventional cytotoxic drugs used to treat AML, several act by increasing unique types of DNA lesions known as DNA-protein crosslinks (DPCs). In particular, topoisomerase poisons increase the number of DPCs containing TOP2 (daunorubicin, mitoxantrone, etoposide) or TOP1 (topotecan) covalently bound to DNA. In addition, the hypomethylating agents decitabine and azacitidine increase the number of DPCs containing DNA methyltransferases covalently bound to DNA. The mechanisms involved in DPC repair are at present incompletely understood. To facilitate the further development of topotecan and other TOP1 poisons, as well contribute to the study of TOP1-containing DPCs, we have generated an antibody that specifically recognizes TOP1-DNA covalent complexes (TOP1ccs). Using this antibody, we have shown that the nuclear metalloproteinase SPARTAN and the serine protease FAM111A, acting upstream of the phosphodiesterase TDP1, play important roles in the repair of TOP1ccs in some tissues. Importantly, loss of SPARTAN, FAM111A or TDP1 leads to accumulation of TOP1ccs in the absence of drug treatment as well as enhanced sensitivity to the prototypic TOP1 poison camptothecin. More recently, we have also observed that a variety of malignant myeloid cells, including AML cell lines and primary AML specimens, contain readily detectable TOP1ccs in the absence of drug treatment and are slow to repair TOP1ccs upon exposure to the TOP1 poison topotecan. In contrast, the vast majority of tissues, including normal and malignant lymphoid cells as well as normal marrow, contain very few TOP1ccs in the absence of drug treatment. These results lead to the hypothesis that many myeloid neoplasms have previously unsuspected defects in TOP1cc repair that might affect their therapeutic sensitivity. To test this hypothesis, we now propose to define the biochemical basis for the constitutive increase in TOP1ccs in myeloid neoplasms (Aim 1), examine the impact of low TOP1cc repair on leukemia cell sensitivity to agents that stabilize DPCs (Aim 2), and assess the relationship between TOP1cc levels (constitutive and drug-induced) and clinical response of myeloid neoplasms to a topotecan-containing regimen currently undergoing NCI-sponsored phase II clinical testing in high risk AML (Aim 3). Collectively, these studies will provide important new insight into a previously unsuspected DPC repair defect in myeloid malignancies and begin to determine whether this repair defect has therapeutic implications that can be used to guide improvements in AML therapy.

抽象的急性髓样白血病（AML）是克隆造血疾病的遗传异质群以未成熟的非淋巴骨髓祖细胞的积累为特征。虽然有著名的在过去的5年中，治疗性进展，许多AML亚型的病例死亡率> 50％。尽管引入了多种靶向疗法，但单独或中的常规细胞毒性药物与靶向药物的结合 - 仍然是AML治疗的中流。在常规细胞毒性中用于治疗AML的药物，通过增加了独特类型的DNA病变，称为DNA-蛋白交叉链接（DPC）。特别是，拓扑异构酶毒物增加了包含TOP2的DPC的数量（daunorubicin，mitoxantrone，依托泊剂）或TOP1（拓扑替克）与DNA共同结合。另外，低甲基化剂decideabine和azacitidine增加了含有DNA的DPC的数量甲基转移酶共价结合到DNA。目前，DPC修复中涉及的机制不完全理解。为了促进拓扑丹和其他Top1毒物的进一步发展为含TOP1的DPC的研究做出贡献，我们产生了一种明确识别的抗体 TOP1-DNA共价复合物（TOP1CCS）。使用这种抗体，我们表明核金属蛋白酶spartan和丝氨酸蛋白酶FAM111a，作用于磷酸二酯酶上游 TDP1，在某些组织中TOP1CC的修复中起重要作用。重要的是，斯巴达人的丧失，FAM111A 或TDP1在没有药物治疗的情况下导致TOP1CC的积累以及对原型TOP1毒药camptothecin。最近，我们还观察到各种恶性肿瘤包括AML细胞系和主要AML样品在内缺乏药物治疗，在暴露于TOP1毒药拓扑替康时修复TOP1CC的速度很慢。对比，绝大多数组织，包括正常和恶性淋巴样细胞以及正常骨髓，在没有药物治疗的情况下，很少有Top1ccs。这些结果导致了以下假设髓样瘤治疗灵敏度。为了检验这一假设，我们现在建议定义髓样肿瘤中TOP1CC的组成型增加（AIM 1），检查低top1cc修复的影响白血病细胞对稳定DPC的药物的敏感性（AIM 2），并评估TOP1CC之间的关系髓样肿瘤对含拓扑替康的水平（组成型和药物诱导的）和临床反应目前正在进行NCI赞助的II期临床测试中的方案（AIM 3）。共同这些研究将为髓样中的先前未刺的DPC修复缺陷提供重要的新见解 Malignancys并开始确定该修复缺陷是否具有可以使用的热含义指导AML治疗的改进。