EVI1 Expression is a Prognostic Marker of CML

描述（由申请人提供）：慢性骨髓性白血病（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。这个可治疗的阶段通常持续2-5年，但如果不治疗，它将不可避免地发展到最后的爆炸（或加速）阶段，对此没有已知的治疗方法。EVI 1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STI 571靶向并抑制白血病细胞中的BCP/ABL活性。由于STI 571耐药的频率增加，目前NIH赞助的临床试验研究了STI 571和IFN-α联合治疗CML。EVI 1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EVI 1是一种侵袭性癌基因。我们工作的新进展表明，EVI 1消除了IFN-α在体外的作用，IFN-α耐药慢性期CML患者表达EVI 1，并且在IFN-α造血细胞系中强制表达EVI 1消除了对IFN-α的生长抑制反应。总之，这些数据提供了CML相关基因与IFN-α抑制反应失败之间的第一个明确的相关性。基于上述背景，我们认为不适当表达EVI 1的CML患者对IFN-α单独治疗或与STI 571联合治疗无反应。用STI 571和IFN-α治疗的EVI 1阳性患者实际上也可能受到伤害，因为单独用IFN-α治疗将排除在临床试验中也与STI 571联合使用的替代药物阿糖胞苷的使用。本提案的目的是设计一种敏感的常规检测，以识别表达EVI 1的CML患者，因此他们不会从IFN-α治疗中获益。我们的目标是：首先，我们将确定最佳的实验条件，定量的白血病和对照样品中的EVI 1的表达。第二，我们将确定慢性期患者中EVI 1的表达是否诱导疾病更快地进展到急变期。本研究将使用CML和对照样本的实时RT-PCR分析和统计分析。

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.