Genomic instability causes imatinib resistance in CML

基因组不稳定导致 CML 患者对伊马替尼耐药

• 批准号: 7371454
• 负责人: TOMASZ SKORSKI
• 金额: $ 32.98万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371454
• 关键词: Acute Lymphocytic Leukemia; Acute leukemia; Amino Acid Substitution; Antioxidants; Base Excision Repairs; Bcr-Abl tyrosine kinase; Cells; Chronic; Chronic Myeloid Leukemia; Clinical; DNA Damage; DNA Repair; DNA lesion; Depth; Evaluation; Excision; Frequencies; Functional disorder; Generations; Genes; Genomic Instability; Gleevec; Goals; Hematopoietic stem cells; Imatinib; Imatinib mesylate; Immunofluorescence Immunologic; In Vitro; Investigation; Lead; Modality; Mutagenesis; Mutation; Myeloid Leukemia; Myeloid Progenitor Cells; Numbers; Oncogenic; Patients; Phosphorylation; Phosphotransferases; Process; Protein Tyrosine Kinase; Reaction; Reactive Oxygen Species; Reciprocal Translocation; Reporter; Resistance; Role; STI571; Stem cells; System; Therapeutic; Therapeutic Effect; Transgenic Mice; Uracil; abl Genes; abl Oncogene; aptamer; base; bcr-abl Fusion Proteins; cell transformation; cohort; granulocyte; in vivo Model; inhibitor/antagonist; leukemia; leukemia/lymphoma; leukemogenesis; macrophage; mutant; novel strategies; oxidative DNA damage; prevent; repaired; response; small molecule

DESCRIPTION (provided by applicant): Bcr/abl gene is derived from the t(9;22) reciprocal translocation and is present in most of chronic myelogenous leukemia (CML) and a cohort of acute lymphoblastic leukemia (ALL) patients. BCR/ABL oncogenic tyrosine kinase modulates response to DNA damage inducing resistance to genotoxic therapies. In addition BCR/ABL stimulates genomic instability, which may lead to mutations in BCR/ABL kinase causing resistance to imatinib mesylate. We hypothesize that: BCR/ABL elevates the levels of reactive oxygen species (ROS) which induce "spontaneous" DNA lesions (for example uracil residues), whose unfaithful repair introduces amino acid substitutions in the BCR/ABL kinase domain causing resistance to IM. The role of ROS in generation of oxidative DNA damage leading to mutagenesis and resistance to imatinib mesylate will be studied in CML hematopoietic stem cells (HSC), common myeloid progenitor cells (CMP), and granulocyte/macrophage progenitor cells (GMP) using anti-oxidant approaches and in vitro and in vivo models of BCR/ABL leukemogenesis. The efficiency and fidelity of the mechanisms processing ROS-dependent oxidative DNA damage in BCR/ABL leukemia cells will be determined by studying base excision repair (BER), focusing on UDG glycosylase removing uracil residues. These reactions will be examined using well-defined reporter/substrate systems and a combination of different approaches including immunofluorescence, phosphorylation-less and interaction- deprived mutants, transgenic mice, and sequencing. BCR/ABL-UDG functional interaction will be investigated by mutagenesis and targeted by aptamers to inhibit resistance to imatinib mesylate. Imatinib mesylate (IM) revolutionized the treatment of BCR/ABL-positive leukemias such as chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemias (ALL). Unfortunately, reactive oxygen species (ROS) cause amino acid substitutions in the BCR/ABL kinase domain resulting in resistance to IM. We will determine if anti-oxidants are able to reduce mutations and IM resistance. In addition, we will examine the role of base excision repair in generation of these mutations. Results of our studies may lead to better treatment of BCR/ABL-positive leukemias.

描述（由申请人提供）：BCR/ABL基因源自T（9; 22）相互易位，并且存在于大多数慢性髓性白血病（CML）和急性淋巴细胞性白血病（ALL）患者中。 BCR/ABL致癌酪氨酸激酶调节对DNA损伤的反应，诱导对遗传毒性疗法的抗性。另外，BCR/ABL刺激了基因组不稳定性，这可能导致BCR/ABL激酶的突变，从而导致甲基酸伊马替尼的抗性。我们假设：BCR/ABL提高了诱导“自发” DNA病变（例如尿嘧啶残基）的活性氧（ROS）的水平，其不忠的维修在BCR/ABL激酶域中引入氨基酸取代，从而引起对IM的抗性。 ROS在CML造血干细胞（HSC），常见的髓样祖细胞（CMP）和颗粒细胞/巨噬细胞（GMP）中使用抗氧化剂和抗氧化剂的VivEs和Viver ins in vriv viv viv，ROS在CML造血干细胞（HSC），常见的髓样祖细胞（CMP）中的作用将在CML造血干细胞（HSC），常见的髓样祖细胞（CMP）和使用抗氧化剂的VivEs in Viver in vercl of ver-nofe and ver-nofe n ver中研究。在BCR/ABL白血病细胞中处理ROS依赖性DNA损伤的机制的效率和保真度将通过研究碱切除修复（BER）来确定，重点是去除UDG糖基化酶去除尿嘧啶残基。这些反应将使用明确定义的报告基因/底物系统以及包括免疫荧光，无磷酸化和相互作用的剥夺突变体，转基因小鼠和测序的不同方法的组合进行检查。 BCR/ABL-UDG功能相互作用将通过诱变进行研究，并由适体靶向抑制对伊马替尼梅赛酸盐的抗性。伊马替尼（Imatinib）梅赛酸盐（IM）彻底改变了对BCR/ABL阳性白血病的治疗，例如慢性粒细胞性白血病（CML）和一系列急性淋巴细胞性白血病（全部）。不幸的是，活性氧（ROS）在BCR/ABL激酶结构域中引起氨基酸取代，从而导致对IM的抗性。我们将确定抗氧化剂是否能够降低突变和IM耐药性。此外，我们将研究基础切除修复在这些突变的产生中的作用。我们的研究结果可能会导致更好地治疗BCR/ABL阳性白血病。