High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia
High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia
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DOI：
10.1182/blood-2009-02-206722
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发表时间：
2009-07-16
期刊：
影响因子：
20.3
通讯作者：
Look, A. Thomas
中科院分区：
文献类型：
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作者：
Gutierrez, Alejandro;Sanda, Takaomi;Look, A. Thomas
为了更全面地评估PTEN-PI 3 K-AKT通路对T细胞急性淋巴细胞白血病（T-ALL）的致病作用，我们使用阵列比较基因组杂交和序列分析检查了T-ALL儿童的诊断DNA样本。在44例病例中，47.7%的病例发现了PTEN、PI 3 K或AKT的改变。在12例病例中，外显子7中存在显著的PTEN突变聚集，所有这些突变都被预测为截短C2结构域而不破坏PTEN的磷酸酶结构域。诱导化疗未能诱导缓解的4例患者中的3例淋巴母细胞携带的PTEN缺失在诊断时，相比之下，没有12例患者与突变的PTEN外显子7（P = 0.007），这表明，PTEN缺失有更多的不利的治疗后果比突变破坏，保留磷酸酶结构域。这些发现为开发靶向T-ALL中PTEN-PI 3 K-AKT通路的疗法的理论基础提供了重要支持。（血。2009; 114：647-650）
To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL. (Blood. 2009; 114: 647-650)