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

染色体易位t(9；22)是编码bcr/abl融合癌基因出现的原因。 酪氨酸激酶，可诱发慢性粒细胞白血病(CML)和一组急性淋巴细胞 白血病(ALL)。CML通常始于相对良性的慢性期(CML-CP)，进展为 侵袭性疾患危机(CML-BC)。这种疾病的恶变与 累积额外的遗传错误。 甲磺酸伊马替尼(IM)是一种BCR/ABL激酶的小分子抑制剂，它彻底改变了BCR/ABL激酶的治疗方法。 慢性粒细胞白血病-慢性粒细胞白血病。不幸的是，患者可能会因编码点突变而对药物产生抗药性。 Bcr/abl激活区的氨基酸替换。 综上所述，CML细胞表现出基因组不稳定性，导致对IM和恶性疾病的抵抗 疾病的发展。这项建议的重点是确定负责这些问题的机制 这些现象以及随后关于预防/抑制IM耐药和CML-BC的发展。 BCR/ABL激酶激活多种信号通路诱导和维持细胞转化 造血细胞。我们和其他人发现磷脂酰肌醇-3激酶(PI-3K)在 慢性粒细胞白血病中生长因子非依赖性增殖和抗凋亡作用。 在这里，我们建议研究PI-3K及其下游效应因子Akt和Rac在基因组中的作用 慢性粒细胞白血病干细胞和祖细胞群体的不稳定性。使用遗传方法(显性-负性突变体， SiRNA、反义cdna、基因敲除小鼠)和小分子抑制剂(例如周福辛、NSC23766)。 将决定PI-3K及其下游效应器如何产生活性氧物种(ROS)，这在 TURN可能导致DNA氧化损伤，促进基因组不稳定。长期体外培养与小鼠 CML的模型将在这里应用。免疫球蛋白耐药性将通过克隆试验和测序进行检测 SNPs和Sky将检测到BCR/ABL激活区和染色体的异常。 如果成功完成，这些实验将确定PI-3k途径抑制剂是否应该 用于提高IM的治疗效果，防止/延缓CML进展为致命性急变。

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.