Abramowitz Julia, Neuman Tzahi, Perlman Riki, Ben-Yehuda Dina
Department of Hematology, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem, 91120, Israel.
Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
BMC Med Genomics. 2017 Mar 24;10(1):18. doi: 10.1186/s12920-017-0249-2.
Mechanisms that inactivate the p53 pathway in Acute Myeloid Leukemia (AML), other than rare mutations, are still not well understood.
We performed a bioinformatics study of the p53 pathway function at the gene expression level on our collection of 1153 p53-pathway related genes. Publically available Affymetrix data of 607 de-novo AML patients at diagnosis were analyzed according to the patients cytogenetic, FAB and molecular mutations subtypes. We further investigated the functional status of the p53 pathway in cytogenetically normal AML (CN-AML) and Acute Promyelocytic Leukemia (APL) patients using bioinformatics, Real-Time PCR and immunohistochemistry.
We revealed significant and differential alterations of p53 pathway-related gene expression in most of the AML subtypes. We found that p53 pathway-related gene expression was not correlated with the accepted grouping of AML subtypes such as by cytogenetically-based prognosis, morphological stage or by the type of molecular mutation. Our bioinformatic analysis revealed that p53 is not functional in CN-AML and APL blasts at inducing its most important functional outcomes: cell cycle arrest, apoptosis, DNA repair and oxidative stress defense. We revealed transcriptional downregulation of important p53 acetyltransferases in both CN-AML and APL, accompanied by increased Mdmx protein expression and inadequate Chk2 protein activation.
Our bioinformatic analysis demonstrated that p53 pathway is differentially inactivated in different AML subtypes. Focused gene and protein analysis of p53 pathway in CN-AML and APL patients imply that functional inactivation of p53 protein can be attributed to its impaired acetylation. Our analysis indicates the need in further accurate evaluation of p53 pathway functioning and regulation in distinct subtypes of AML.
除了罕见突变外，急性髓系白血病（AML）中使p53通路失活的机制仍未完全明确。
我们对收集的1153个与p53通路相关的基因进行了基因表达水平上的p53通路功能生物信息学研究。根据患者的细胞遗传学、FAB分型和分子突变亚型，分析了607例初诊急性髓系白血病患者公开可用的Affymetrix数据。我们进一步使用生物信息学、实时荧光定量PCR和免疫组织化学方法，研究了细胞遗传学正常的急性髓系白血病（CN-AML）和急性早幼粒细胞白血病（APL）患者中p53通路的功能状态。
我们发现大多数AML亚型中p53通路相关基因表达存在显著且不同的改变。我们发现p53通路相关基因表达与基于细胞遗传学的预后、形态学分期或分子突变类型等公认的AML亚型分组无关。我们的生物信息学分析表明，在CN-AML和APL原始细胞中，p53在诱导其最重要的功能结果（细胞周期阻滞、凋亡、DNA修复和氧化应激防御）方面无功能。我们发现CN-AML和APL中重要的p53乙酰转移酶转录下调，同时Mdmx蛋白表达增加且Chk2蛋白激活不足。
我们的生物信息学分析表明，p53通路在不同的AML亚型中以不同方式失活。对CN-AML和APL患者p53通路进行聚焦的基因和蛋白质分析表明，p53蛋白的功能失活可归因于其乙酰化受损。我们的分析表明，需要进一步准确评估p53通路在不同AML亚型中的功能和调控。
