Co-existence of PHF6 and NOTCH1 mutations in adult T-cell acute lymphoblastic leukemia.
Co-existence of PHF6 and NOTCH1 mutations in adult T-cell acute lymphoblastic leukemia.
复制标题
成人 T 细胞急性淋巴细胞白血病中 PHF6 和 NOTCH1 突变共存。
DOI：
10.3892/ol.2016.4581
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发表时间：
2016-07
期刊：
影响因子：
2.9
通讯作者：
Ge Z
中科院分区：
文献类型：
--
作者：
Li M;Xiao L;Xu J;Zhang R;Guo J;Olson J;Wu Y;Li J;Song C;Ge Z
T细胞急性淋巴细胞白血病(T-ALL)是T细胞前体细胞转化过程中多种基因异常协同作用的结果。植物同源结构域手指蛋白6(PHF6)是一种关键的肿瘤抑制基因，在T-ALL中发生突变，但在成人T-ALL中的临床意义尚未完全确定。在本研究中，通过扩增PHF6外显子，然后进行DNA测序，以确定基因组突变并检测成人T-ALL患者PHF6的表达。用χ-2检验分析PHF6基因突变与临床特征的相关性，用Kaplan-Meier方法分析PHF6基因突变与生存曲线的相关性。在中国成人T-ALL患者中，27.1%(16/59)检测到PHF6突变，其中10例为新突变。PHF6突变的T-ALL患者PHF6的表达水平明显低于无突变的T-ALL患者。在观察到的PHF6突变中，6/16是移码突变，表明这些患者存在PHF6功能障碍。值得注意的是，PHF6突变被发现与年龄较大、血红蛋白水平较低、CD13阳性率较高以及脾肿大或淋巴结病的发生率较高显著相关。此外，还发现PHF6突变与Notch同源基因1，易位相关(果蝇)(NOTCH1)突变显著相关。同时存在两种突变的T-ALL患者无事件生存期明显缩短，预后较差。目前的结果表明，PHF6在成人T-ALL中是失活的，这是由于其低表达和突变所致。目前的数据表明，PHF6和NOTCH1突变以及它们的共存在成人T-ALL的致癌作用中具有协同作用，并且它们可能成为该疾病的预后标志。
T-cell acute lymphoblastic leukemia (T-ALL) results from the collaboration of multiple genetic abnormalities in the transformation of T-cell progenitors. Plant homeodomain finger protein 6 (PHF6) has recently been established as a key tumor suppressor, which is mutated in T-ALL; however, the clinical significance of PHF6 mutations has not been fully determined in adult T-ALL. In the present study, amplification of the PHF6 exons was performed, followed by DNA sequencing to identify the genomic mutations and examine the expression of PHF6 in adult patients with T-ALL. The correlation between PHF6 mutations and clinical features was also analyzed using a χ2 test, and between PHF6 mutations and survival curve using the Kaplan-Meier methods. PHF6 mutations were detected in 27.1% of the Chinese adults with T-ALL (16/59), 10 of which were found to be novel mutations. A significantly lower expression level of PHF6 was observed in T-ALL patients with PHF6 mutations compared with those without mutations. Of the observed mutations in PHF6, 6/16 were frame-shift mutations, indicating a PHF6 dysfunction in those patients. Of note, PHF6 mutations were found to be significantly associated with older age, lower hemoglobin levels, higher frequency of CD13 positivity and higher incidence of splenomegaly or lymphadenopathy. Furthermore, PHF6 mutations were found to be significantly correlated with Notch homolog 1, translocation-associated (Drosophila) (NOTCH1) mutations. The patients with T-ALL with co-existence of the two mutations had a significantly shorter event-free survival and a poor prognosis. The present results indicated that PHF6 is inactivated in adult T-ALL, due to its low expression and mutations. The present data indicated the synergistic effect of PHF6 and NOTCH1 mutations, as well as their co-existence, on the oncogenesis of adult T-ALL, and their potential as a prognostic marker for the disease.