Lugthart Sanne, van Drunen Ellen, van Norden Yvette, van Hoven Antoinette, Erpelinck Claudia A J, Valk Peter J M, Beverloo H Berna, Löwenberg Bob, Delwel Ruud
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Blood. 2008 Apr 15;111(8):4329-37. doi: 10.1182/blood-2007-10-119230. Epub 2008 Feb 13.
Inappropriate expression of EVI1 (ecotropic virus integration-1), in particular splice form EVI1-1D, through chromosome 3q26 lesions or other mechanisms has been implicated in the development of high-risk acute myeloid leukemia (AML). To validate the clinical relevance of EVI1-1D, as well as of the other EVI1 splice forms and the related MDS1/EVI1 (ME) gene, real-time quantitative polymerase chain reaction was performed in 534 untreated adults with de novo AML. EVI1-1D was highly expressed in 6% of cases (n = 32), whereas 7.8% were EVI1(+) (n = 41) when all splice variants were taken into account. High EVI1 predicted a distinctly worse event-free survival (HR = 1.9; P = .002) and disease-free survival (HR = 2.1, P = .006) following multivariate analysis. Importantly, we distinguished a subset of EVI1(+) cases that lacked expression of ME (EVI1(+)ME(-); n = 17) from cases that were ME(+) (EVI1(+)ME(+); n = 24). The atypical EVI1(+)ME(-) expression pattern exhibited cytogenetically detectable chromosomal 3q26 breakpoints in 8 cases. Fluorescence in situ hybridization revealed 7 more EVI1(+)ME(-) cases that carried cryptic 3q26 breakpoints, which were not found in the EVI1(+)ME(+) group. EVI1(+)ME(-) expression predicts an extremely poor prognosis distinguishable from the general EVI1(+) AML patients (overall survival [OS]: P < .001 and event-free survival [EFS]: P = .002). We argue that EVI1/ME quantitative expression analysis should be implemented in the molecular diagnostic procedures of AML.
通过3号染色体q26位点病变或其他机制导致的EVI1（嗜异性病毒整合位点1），特别是剪接形式EVI1-1D的不适当表达，与高危急性髓系白血病（AML）的发生有关。为了验证EVI1-1D以及其他EVI1剪接形式和相关MDS1/EVI1（ME）基因的临床相关性，对534例未经治疗的初发AML成年患者进行了实时定量聚合酶链反应。EVI1-1D在6%的病例（n = 32）中高表达，而当考虑所有剪接变体时，7.8%的病例EVI1呈阳性（n = 41）。多变量分析显示，高EVI1表达预示无事件生存期（HR = 1.9；P = .002）和无病生存期（HR = 2.1，P = .006）明显更差。重要的是，我们区分了一部分EVI1阳性但缺乏ME表达的病例（EVI1(+)ME(-)；n = 17）和ME阳性的病例（EVI1(+)ME(+)；n = 24）。非典型的EVI1(+)ME(-)表达模式在8例病例中表现为细胞遗传学可检测到的3号染色体q26断点。荧光原位杂交显示，另有7例EVI1(+)ME(-)病例携带隐匿性3号染色体q26断点，而在EVI1(+)ME(+)组中未发现此类情况。EVI1(+)ME(-)表达预示预后极差，与一般EVI1阳性的AML患者不同（总生存期[OS]：P < .001；无事件生存期[EFS]：P = .002）。我们认为，EVI1/ME定量表达分析应纳入AML的分子诊断程序。
