"BCR/ABL-PI-3k-ROS pathway induce genomic instability ...."

“BCR/ABL-PI-3k-ROS 通路导致基因组不稳定......”

• 批准号: 8271268
• 负责人: TOMASZ SKORSKI
• 金额: $ 30.8万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271268
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute Lymphocytic Leukemia; Amino Acid Substitution; Apoptosis; Appearance; Benign; Biological; Biological Assay; Blast Phase; Cell Proliferation; Cells; Chromosomal translocation; Chromosome abnormality; Chronic Myeloid Leukemia; Chronic Phase; Chronic-Phase Myeloid Leukemia; Complementary DNA; Complex; DNA Repair; Development; Disease; Disease Progression; Dominant-Negative Mutation; Drug resistance; Extracellular Matrix; Figs - dietary; Generations; Genetic; Genomic Instability; Growth Factor; Hematopoietic; Hematopoietic stem cells; Imatinib; Imatinib mesylate; In Vitro; Knockout Mice; Laboratories; Malignant - descriptor; Mediating; Mitochondria; Molecular; Mutation; Myelogenous; NADPH Oxidase; Oncogenes; Oncogenic; Pathway interactions; Patients; Perifosine; Phosphatidylinositols; Phosphotransferases; Play; Point Mutation; Population; Prevention; Production; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proteins; Reactive Oxygen Species; Reporting; Resistance; Resistance development; Respiratory Chain; Role; Signal Pathway; Small Interfering RNA; Source; Stem cells; Therapeutic Effect; Tyrosine Kinase Inhibitor; Work; bcr-abl Fusion Proteins; cohort; granulocyte; improved; inhibitor/antagonist; leukemia; leukemic stem cell; leukemogenesis; macrophage; mouse model; mutant; novel strategies; oxidative DNA damage; prevent; progenitor; rac GTP-Binding Proteins; research study; small molecule; stem

Chromosomal translocation t(9;22) is responsible for appearance of an oncogene encoding BCR/ABL fusion tyrosine kinase, which induce chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemia (ALL). CML usually starts as a relatively benign chronic phase (CML-CP), which progresses to an aggressive disease - blast crisis (CML-BC). Malignant transformation of the disease is associated with accumulation of additional genetic errors. Imatinib mesylate (IM), a small molecule inhibitor of BCR/ABL kinase, revolutionized the treatment of CML-CP. Unfortunately patients may develop resistance to the drug caused by point mutations encoding amino acid substitutions in the BCR/ABL kinase domain. In conclusion, CML cells display genomic instability leading to resistance to IM and malignant progression of the disease. This proposal is focused on determination the mechanisms responsible for these phenomena and subsequently on prevention/inhibition of the development of IM resistance and CML-BC. BCR/ABL kinase stimulates numerous signaling pathways to induce and maintain transformation of hematopoietic cells. We, and others found that phosphatidylinositol-3 kinase (PI-3k) play an essential role in growth factor independent proliferation and protection from apoptosis in CML. Here we propose to study the role of PI-3k and its downstream effectors Akt and Rac in genomic instability in CML stem and progenitor cell populations. Using genetic approach (dominant-negative mutants, siRNA, antisense cDNA, knockout mice) and small molecule inhibitors (for example perifosine, NSC23766) we will determine how PI-3k and its downstream effectors generate the reactive oxygen species (ROS), which in turn may cause oxidative DNA damage and facilitate genomic instability. Long-term in vitro culture and mouse models of CML will be applied here. IM resistance will be detected in clonogenic assays and by sequencing BCR/ABL kinase domain, and chromosomal aberrations will be detected by SNPs and SKY. If successfully accomplished, these experiments will determine if PI-3k pathway inhibitors should be used to improve therapeutic effect of IM and prevent/delay CML progression toward lethal blast crisis.

染色体易位t（9;22）是编码BCR/ABL融合的癌基因出现的原因