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）：慢性粒细胞白血病（CML）是一种以初始慢性期为特征的疾病，在此期间存在骨髓细胞谱系的异常增殖。这个可治疗的阶段一般持续 2-5 年，但如果不进行治疗，它将不可避免地进展到最终的急变（或加速）阶段，而目前尚无已知的治疗方法。 EVI1基因的异常表达出现在大多数CML患者中。长期以来，CML 的首选治疗方法是 IFN-α，但最近有一种新药 STI571，靶向并抑制白血病细胞中的 BCP/ABL 活性。由于 STI571 耐药性频率不断增加，目前 NIH 资助的临床试验研究 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。我们证明 EVI1 是一种侵袭性癌基因。我们工作的新进展表明EVI1在体外消除了IFN-α的作用，IFN-α抵抗的慢性期CML患者表达EVI1，并且在IFN-α造血细胞系中强制表达EVI1消除了生长抑制对 IFN-α 的反应。总而言之，这些数据首次提供了 CML 相关基因与对 IFN-α 抑制反应失败之间的明确关联。根据所提出的背景，我们建议不适当表达 EVI1 的 CML 患者不会对单独的 IFN-α 治疗或与 STI571 联合治疗产生反应。使用 STI571 和 IFN-α 治疗的 EVI1 阳性患者实际上也可能受到伤害，因为单独使用 IFN 治疗将排除使用替代药物阿糖胞苷（也在临床试验中与 STI571 联合使用）。该提案的目标是设计一种敏感的常规测试来识别表达 EVI1 且因此不会从 IFN-α 治疗中受益的 CML 患者。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，我们将确定慢性期患者中的 EVI1 表达是否会导致疾病更快地进展至急变期。本研究将使用 CML 和对照样本的实时 RT-PCR 分析和统计分析。