BCL2 Inhibitor (ABT-737): A Restorer of Prednisolone Sensitivity in Early T-Cell Precursor-Acute Lymphoblastic Leukemia with High MEF2C Expression?
BCL2 Inhibitor (ABT-737): A Restorer of Prednisolone Sensitivity in Early T-Cell Precursor-Acute Lymphoblastic Leukemia with High MEF2C Expression?
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DOI：
10.1371/journal.pone.0132926
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hosoi H
中科院分区：
文献类型：
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作者：
Kawashima-Goto S;Imamura T;Tomoyasu C;Yano M;Yoshida H;Fujiki A;Tamura S;Osone S;Ishida H;Morimoto A;Kuroda H;Hosoi H
早期T细胞急性淋巴细胞白血病（ETP-ALL）已被确定为儿童T细胞急性淋巴细胞白血病（T-ALL）的高危亚型。常规化疗对这种白血病亚型并不完全有效;因此，需要探索潜在的治疗靶点。对儿童T-ALL中转录因子基因表达模式的分析显示，MEF 2C和FLT 3在ETP-ALL中的表达水平高于典型的T-ALL。本研究使用MEF 2C高表达水平的人T-ALL和BaF 3细胞系，测试BCL 2抑制剂（ABT-737）是否恢复对泼尼松龙（PSL）的敏感性，因为MEF 2C可能通过增强BCL 2的抗凋亡活性而引起PSL抗性。用PSL和ABT-737处理导致除了MEF 2C转导的BaF 3细胞之外，在表达MEF 2C的LOUCY细胞中PSL的IC 50显著降低，但在不表达MEF 2C的Jurkat细胞中没有。联合治疗显著加速了与鼠基质细胞共培养的具有高表达水平MEF 2C的ETP-ALL的原代白血病母细胞的杀伤。这些发现表明，BCL 2抑制剂可能是MEF 2C高表达水平的ETP-ALL患者的体内治疗候选药物。
Early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL) has been identified as a high-risk subtype of pediatric T-cell acute lymphoblastic leukemia (T-ALL). Conventional chemotherapy is not fully effective for this subtype of leukemia; therefore, potential therapeutic targets need to be explored. Analysis of the gene expression patterns of the transcription factors in pediatric T-ALL revealed that MEF2C and FLT3 were expressed at higher levels in ETP-ALL than typical T-ALL. Using human T-ALL and BaF3 cell lines with high expression levels of MEF2C, the present study tested whether the BCL2 inhibitor (ABT-737) restores the sensitivity to prednisolone (PSL), because MEF2C causes PSL resistance, possibly by augmenting the anti-apoptotic activity of BCL2. Treatment with PSL and ABT-737 caused a significant reduction in the IC50 of PSL in the MEF2C-expressing LOUCY cells, in addition to the MEF2C-transduced BaF3 cells, but not in the non-MEF2C-expressing Jurkat cells. The combination treatment significantly accelerated the killing of primary leukemic blast cells of ETP-ALL with high expression levels of MEF2C, which were co-cultured with murine stromal cells. These findings suggest that BCL2 inhibitors may be a therapeutic candidate in vivo for patients with ETP-ALL with high expression levels of MEF2C.