Laszlo George S, Alonzo Todd A, Gudgeon Chelsea J, Harrington Kimberly H, Kentsis Alex, Gerbing Robert B, Wang Yi-Cheng, Ries Rhonda E, Raimondi Susana C, Hirsch Betsy A, Gamis Alan S, Meshinchi Soheil, Walter Roland B
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D2-190, Seattle, WA, 98109-1024, USA.
Department of Biostatistics, University of Southern California, Los Angeles, CA, USA.
J Hematol Oncol. 2015 Oct 20;8:115. doi: 10.1186/s13045-015-0215-4.
Recent studies have identified myocyte enhancer factor 2C (MEF2C) as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML, raising the possibility that MEF2C could serve as marker of poor-risk AML and, therefore, have prognostic significance.
To test this hypothesis, we retrospectively quantified MEF2C expression in pretreatment bone marrow specimens in participants of the AAML0531 trial by reverse-transcriptase polymerase chain reaction and correlated expression levels with disease characteristics and clinical outcome.
In all 751 available patient specimens, MEF2C messenger RNA (mRNA) was detectable and varied >3000-fold relative to β-glucuronidase. Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67 vs. 78 %, P = 0.005). They also had an inferior overall survival (P = 0.014; at 5 years 55 ± 8 vs. 67 ± 4 %), inferior event-free survival (P < 0.001; at 5 years 38 ± 7 vs. 54 ± 4 %), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P < 0.001; at 5 years 53 ± 9 vs. 35 ± 5 %). These differences were accounted for by lower prevalence of cytogenetically/molecularly defined low-risk disease (16 vs. 46 %, P < 0.001) and higher prevalence of standard-risk disease (68 vs. 42 %, P < 0.001) in patients with high MEF2C expression, suggesting that MEF2C cooperates with additional pathogenic abnormalities.
High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. With confirmation that high MEF2C mRNA expression leads to overexpression of MEF2C protein, these findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML.
最近的研究已确定肌细胞增强因子2C（MEF2C）是急性髓系白血病（AML）中的协同致癌基因，并提示其对至少某些AML亚型的侵袭性有影响，这增加了MEF2C可作为高危AML标志物并因此具有预后意义的可能性。
为验证这一假设，我们通过逆转录聚合酶链反应对AAML0531试验参与者预处理骨髓标本中的MEF2C表达进行回顾性定量，并将表达水平与疾病特征和临床结局相关联。
在所有751份可用患者标本中，均可检测到MEF2C信使核糖核酸（mRNA），其相对于β-葡萄糖醛酸酶的变化超过3000倍。MEF2C相对表达最高（第4四分位数）的患者在一个疗程化疗后实现完全缓解的可能性低于其他患者（67%对78%，P = 0.005）。他们的总生存期也较差（P = 0.014；5年时为55±8%对67±4%），无事件生存期较差（P < 0.001；5年时为38±7%对54±4%），且复发风险高于MEF2C表达较低的3个四分位数范围内的患者（P < 0.001；5年时为53±9%对35±5%）。这些差异是由于MEF2C高表达患者中细胞遗传学/分子定义的低危疾病患病率较低（16%对46%，P < 0.001）以及标准风险疾病患病率较高（68%对42%，P < 0.001），这表明MEF2C与其他致病异常协同作用。
MEF2C高表达可识别出具有不良风险疾病特征和不良结局的AML患者亚组。随着MEF2C高mRNA表达导致MEF2C蛋白过表达得到证实，这些发现为AML中MEF2C转录激活的治疗靶向提供了理论依据。
