EVI1 Expression is a Prognostic Marker of CML

EVI1 表达是 CML 的预后标志物

• 批准号: 6610092
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610092
• 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）：慢性粒细胞性白血病（CML）是一种疾病，其特征是初始慢性期，在此期间，髓样细胞谱系异常增殖。这一可治疗阶段通常持续2 - 5年，但是如果没有治疗，它将不可避免地发展为最终的爆炸（或加速）阶段，没有已知的治疗方法。 EVI1基因的不当表达出现在大多数CML患者中。长期以来，CML首选的治疗方法是IFN-Alpha，但是最近一种新药STI571靶向并抑制白血病细胞中的BCP/ABL活性。由于STI571耐药性的频率增加，当前的NIH赞助的临床试验研究了STI571和IFN-Alpha在CML治疗中的组合。在正常造血骨髓中未检测到EVI1基因，但在约30％至80％的CML患者中表达。我们证明EVI1是一种侵略性的致癌基因。我们工作的新进展表明，EVI1消除了IFN-Alpha体外的影响，IFN-ALPHA耐药的慢性慢性期CML患者表达EVI1，并且EVI1在IFN-Al-Al-α造血细胞系中的强迫表达消除了对IFN-Alpha的生长抑制反应。综上所述，这些数据提供了与CML相关基因与未能响应IFN-Alpha抑制作用之间的第一个明确相关性。基于提出的背景，我们建议不恰当表达EVI1的CML患者不会单独对IFN-Alpha治疗反应或与STI571结合反应。实际上，用STI571和IFN-α治疗的EVI1阳性患者实际上可能会受到伤害，因为用IFN-NORONE治疗将排除在临床试验中使用替代药物Cytarabine的治疗，并与STI571结合使用。该提案的目的是设计敏感的常规测试，以识别表达EVI1并且不会从IFN-Alpha疗法中受益的CML患者。目标是：首先，我们将定义最佳的实验条件，以定量白血病和对照样品中EVI1的表达。其次，我们将确定在慢性期患者中的EVI1表达是否会诱导疾病更快地发展到爆炸阶段。本研究将使用实时RT-PCR分析和CML和对照样本的统计分析。