EVI1 Expression is a Prognostic Marker of CML

描述(申请人提供)：慢性粒细胞白血病(CML)是一种疾病，其特征是在最初的慢性期有髓系细胞系的异常增殖。这种可治疗阶段一般持续2-5年，但如果不进行治疗，它将不可避免地进展到最后的冲击期(或加速阶段)，目前还没有已知的治疗方法。EVI1基因的异常表达存在于大多数CML患者中。长期以来，CML的首选治疗方法是干扰素-α，然而最近一种新药STI571靶向并抑制了白血病细胞中的BCP/ABL活性。由于STI571耐药频率的增加，目前由美国国立卫生研究院赞助的临床试验研究STI571和干扰素-α的联合治疗慢性粒细胞白血病。EVI1基因在正常骨髓中未检测到，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在体外取消了干扰素-α的作用，干扰素-α耐药的慢性期CML患者表达EVI1，并且EVI1在干扰素-α造血细胞系中的强制表达取消了对干扰素-α的生长抑制反应。综上所述，这些数据首次明确提供了慢性粒细胞白血病相关基因与干扰素-α抑制反应失败之间的关联。基于本文提出的背景，我们认为不适当表达EVI1的CML患者不会单独接受干扰素-α治疗或与STI571联合治疗。接受STI571和干扰素-α治疗的EVI1阳性患者实际上也可能受到伤害，因为单独使用干扰素治疗将排除将替代药物阿糖胞苷与STI571联合使用的可能性。这项提议的目标是设计一种敏感的常规测试来识别表达EVI1的CML患者，这些患者因此不会从干扰素-α治疗中受益。我们的目标是：首先，我们将确定EVI1在白血病和对照样本中表达的最佳实验条件。其次，我们将确定EVI1在慢性期患者中的表达是否会导致疾病更快地进展到急变期。本研究将采用实时定量RT-PCR方法对慢性粒细胞白血病和对照样本进行分析和统计分析。

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.