EVI1 Expression is a Prognostic Marker of CML

EVI1 表达是 CML 的预后标志物

• 批准号: 6750118
• 负责人: Giuseppina Nucifora
• 金额: $ 15.59万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6750118
• 关键词: chronic myelogenous leukemia; clinical research; diagnosis design /evaluation; drug resistance; gene expression; genetic markers; human subject; interferon alpha; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; oncogenes; polymerase chain reaction

DESCRIPTION (provided by applicant): Chronic myelogenous leukemia (CML) is a disease characterized by an initial chronic phase during which there is an abnormal proliferation of myeloid cell lineage. This treatable phase in general lasts 2-5 years, but without treatment it will inexorably progress to a final blast (or accelerated) phase for which there is no known treatment. The inappropriate expression of the EVI1 gene appears in the majority of CML patients. For a long time, the treatment of choice for CML was IFN-alpha, however recently a new drug, STI571, targets and inhibits the BCP/ABL activity in the leukemic cells. Because of increasing frequency of STI571 resistance, current NIH-sponsored clinical trials study a combination of STI571 and IFN-alpha in treatment of CML. The EVI1 gene is not detected in normal hematopoietic bone marrow but is expressed in about 30% to 80% of CML patients. We showed that EVI1 is an aggressive oncogene. New advances in our work indicate that EVI1 abrogates the effects of IFN-alpha in vitro, that IFN-alpha-resistant chronic phase CML patients express EVI1, and that the forced expression of EVI1 in IFN-alpha hematopoietic cell lines abrogates the growth-inhibitory response to IFN-alpha. Taken together, these data provide the first clear correlation between a CML-associated gene and the failure to respond to IFN-alpha inhibition. Based on the background presented, we propose that CML patients who inappropriately express EVI1 will not respond to IFN-alpha therapy alone or in combination with STI571. It is also possible that the EVI1-positive patients treated with STI571 and IFN-alpha could actually be harmed because treatment with IFN-alone will preclude the use of the alternative drug Cytarabine also used in clinical trials in combination with STI571. The goal of this proposal is to design a sensitive routine test to identify CML patients who express EVI1 and who therefore will not benefit from IFN-alpha therapy. The goals are: First, we will define the best experimental conditions for quantification of the expression of EVI1 in leukemia and control samples. Second, we will determine whether EVI1 expression in chronic phase patients induces a faster progression of the disease to the blast phase. Real-time RT-PCR analysis and statistical analysis of CML and control samples will be used for this study.

描述（由申请人提供）：慢性髓性白血病（CML）是一种以初始慢性期为特征的疾病，在慢性期存在髓系细胞谱系的异常增殖。这个可治疗的阶段通常持续2-5年，但如果不进行治疗，它将不可避免地发展到最后的爆炸（或加速）阶段，目前尚无治疗方法。EVI1基因的不适当表达出现在大多数CML患者中。长期以来，CML的治疗选择是ifn - α，然而最近一种新药STI571靶向并抑制白血病细胞中的BCP/ABL活性。由于STI571耐药的频率越来越高，目前nih资助的临床试验研究了STI571和ifn - α联合治疗CML。EVI1基因在正常造血骨髓中未检测到，但在约30%至80%的CML患者中表达。我们发现EVI1是一种侵袭性癌基因。我们工作的新进展表明，EVI1在体外可消除ifn - α的作用，ifn - α耐药的慢性期CML患者表达EVI1，并且在ifn - α造血细胞系中强制表达EVI1可消除对ifn - α的生长抑制反应。综上所述，这些数据首次提供了cml相关基因与ifn - α抑制反应失败之间的明确相关性。基于上述背景，我们认为不适当表达EVI1的CML患者对ifn - α单独或联合STI571治疗均无应答。也有可能使用STI571和ifn - α治疗的evi1阳性患者实际上可能受到伤害，因为单独使用ifn治疗将排除替代药物阿糖胞苷的使用，该药物也在临床试验中与STI571联合使用。本提案的目标是设计一个敏感的常规测试来识别表达EVI1的CML患者，因此不能从ifn - α治疗中获益。目标是：首先，我们将确定量化白血病和对照样本中EVI1表达的最佳实验条件。其次，我们将确定在慢性期患者中EVI1的表达是否诱导疾病更快地进展到原胚期。本研究将采用Real-time RT-PCR分析和CML及对照样本的统计分析。