Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia
Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia
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DOI：
10.1002/pbc.24034
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发表时间：
2012-07-01
影响因子：
3.2
通讯作者：
Morishima, Tsuneo
中科院分区：
文献类型：
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作者：
Morishita, Naoto;Tsukahara, Hirokazu;Morishima, Tsuneo
背景 磷酸肌醇 3-激酶 (PI3K)/Akt 途径（一种促生存途径）的激活在肿瘤细胞生长中发挥重要作用。然而，Akt 在儿童 B 前体急性淋巴细胞白血病 (B-pre ALL) 发病机制中的作用仍有待阐明。本研究旨在探讨儿科 B-pre ALL 中 Akt（即磷酸化 Akt、P-Akt）激活的临床相关性和分子机制。程序 我们评估了 21 名新诊断的 B-pre ALL 儿童的骨髓样本中 Akt 的激活状态，并将 P-Akt 的表达水平与临床病理和预后特征相关联。此外，我们将肉豆蔻酰化的 Akt cDNA 转染到 B-pre ALL 细胞系 Nalm-6 中，并在体外检查 Akt 激活对抗肿瘤药物反应的影响。结果 B-pre ALL 患者诊断时 B-pre ALL 母细胞中的 P-Akt 表达与诱导化疗（包括泼尼松龙、地塞米松、长春新碱和阿霉素）反应不佳显着相关。 P-Akt 表达患者的总生存期和无复发生存期均比不表达 P-Akt 的患者显着降低。 Akt 的激活降低了上述 Nalm-6 中抗肿瘤药物诱导的细胞凋亡的程度。 Akt 的激活不会诱导 P-糖蛋白的表达，P-糖蛋白是一种能够赋予多药耐药性的药物转运蛋白。结论 这些结果支持 Akt 激活是 B-pre ALL 化疗耐药机制的论点，并表明 Akt 可以作为治疗复发或难治性儿童 B-pre ALL 的治疗靶点。儿科血癌2012； 59：8389。(C) 2011 Wiley 期刊公司。
Background Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL. Procedure We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs. Results P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance. Conclusion These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL. Pediatr Blood Cancer 2012; 59: 8389. (C) 2011 Wiley Periodicals, Inc.