A novel maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome-positive acute lymphoblastic leukemia.
A novel maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome-positive acute lymphoblastic leukemia.
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DOI：
10.1182/blood-2003-06-1948
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发表时间：
2004-07
期刊：
影响因子：
20.3
通讯作者：
Y. Soda;K. Tani;Yuansong Bai;M. Saiki;Minghan Chen;K. Izawa;Seiichiro Kobayashi;Satoshi Takahashi-Satoshi-Takaha
中科院分区：
文献类型：
--
作者：
Y. Soda;K. Tani;Yuansong Bai;M. Saiki;Minghan Chen;K. Izawa;Seiichiro Kobayashi;Satoshi Takahashi-Satoshi-Takaha
费城染色体阳性（Ph（+））急性淋巴细胞白血病（ALL）患者通常预后不良，并将受益于新的治疗方法的发展。我们以前证明，变构可控的核酶，大酶（Mz），可以诱导慢性粒细胞白血病（CML）细胞凋亡。Ph（+）ALL细胞含有bcrabl融合基因（e1a2），编码参与疾病发病机制的190 kDa融合蛋白（p190）。在这项研究中，我们设计了一种特异性切割e1a2 mRNA的Mz，并使用第三代慢病毒载体系统将此e1a2 Mz转导到Ph（+）ALL细胞中。在5个Ph（+）ALL细胞系中的3个中，e1a2Mz转导导致存活率显著降低和细胞凋亡增加。我们观察到所有用e1a2 Mz转导的Ph（+）ALL细胞中e1a2 mRNA的减少，并且e1a2 Mz抗性细胞中的e1a2 mRNA水平高于e1a2 Mz敏感细胞。检测的所有原代Ph（+）ALL细胞样品均显示e1a2Mz诱导的生长抑制和凋亡。重要的是，e1 a2 Mz不影响正常CD 34（+）脐血细胞的殖民地形成。这些结果表明e1a2Mz对Ph（+）ALL细胞具有特异性杀伤作用，提示它可能成为Ph（+）ALL的一种新的基因治疗策略。
Patients with Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) generally have a poor prognosis and would benefit from the development of new therapeutic approaches. We previously demonstrated that an allosterically controllable ribozyme, maxizyme (Mz), can induce apoptosis in chronic myelogenous leukemia (CML) cells. Ph(+) ALL cells harbor a bcrabl fusion gene (e1a2) encoding a 190-kDa fusion protein (p190) involved in disease pathogenesis. In this study, we have designed a Mz that specifically cleaves e1a2 mRNA and transduced this e1a2Mz into Ph(+) ALL cells using a third-generation lentiviral vector system. In 3 of 5 Ph(+) ALL cell lines, e1a2Mz transduction resulted in a significant decrease in viability and increased cell apoptosis. We observed a decrease in e1a2 mRNA in all Ph(+) ALL cells transduced with e1a2Mz, and the e1a2 mRNA level was higher in e1a2Mz-resistant cells than in e1a2Mz-sensitive cells. All samples of primary Ph(+) ALL cells tested showed e1a2Mz-induced growth inhibition and apoptosis. Importantly, e1a2Mz did not influence the colony formation of normal CD34(+) cord blood cells. These results indicate that e1a2Mz kills Ph(+) ALL cells specifically, suggesting that it may be used as a novel gene therapy strategy for Ph(+) ALL.