Department of Pediatric Oncology/Hematology, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
Leukemia. 2014 Apr;28(4):761-9. doi: 10.1038/leu.2013.245. Epub 2013 Aug 20.
Successful treatment results for MLL-rearranged Acute Lymphoblastic Leukemia (ALL) in infants remain difficult to achieve. Significantly contributing to therapy failure is poor response to glucocorticoids (GCs), like prednisone. Thus, overcoming resistance to these drugs may be a crucial step towards improving prognosis. We defined a gene signature that accurately discriminates between prednisolone-resistant and prednisolone-sensitive MLL-rearranged infant ALL patient samples. In the current study, we applied Connectivity Map analysis to perform an in silico screening for agents capable of reversing the prednisolone-resistance profile and induce sensitivity. These analyses revealed that LY294002, a PI3K inhibitor, would potentially fulfill this task. Subsequent validation experiments demonstrated that indeed LY294002, and other known PI3K inhibitors, markedly sensitized otherwise resistant MLL-rearranged ALL cells to prednisolone in vitro. Using quantitative RT-PCR analyses, we validated the modulating effects of the PI3K inhibitors on the expression of the genes present in our prednisolone-resistance profile. Interestingly, prednisolone-sensitizing actions may be mediated by inhibition of FCGR1B. Moreover, only high-level expression of FCGR1B showed to be predictive for a poor prognosis and shRNA-mediated knock-down of FCGR1B led to in vitro prednisolone sensitization. Thus, implementing FDA-approved PI3K inhibitors in current treatments may potentially improve the GC response and prognosis in patients with MLL-rearranged ALL.
婴儿中 MLL 重排急性淋巴细胞白血病（ALL）的治疗效果仍然难以达到成功。导致治疗失败的一个重要原因是对糖皮质激素（GCs）如泼尼松的反应不佳。因此，克服对这些药物的耐药性可能是改善预后的关键步骤。我们定义了一个基因特征，可以准确地区分泼尼松耐药和泼尼松敏感的 MLL 重排婴儿 ALL 患者样本。在目前的研究中，我们应用连接组学分析进行了计算机筛选，以寻找能够逆转泼尼松耐药谱并诱导敏感性的药物。这些分析表明，PI3K 抑制剂 LY294002 可能能够完成这项任务。随后的验证实验表明，LY294002 和其他已知的 PI3K 抑制剂确实使原本耐药的 MLL 重排 ALL 细胞在体外对泼尼松敏感。通过定量 RT-PCR 分析，我们验证了 PI3K 抑制剂对我们的泼尼松耐药谱中基因表达的调节作用。有趣的是，PI3K 抑制剂的泼尼松增敏作用可能是通过抑制 FCGR1B 介导的。此外，只有高水平表达 FCGR1B 显示与预后不良相关，而 shRNA 介导的 FCGR1B 敲低导致体外泼尼松增敏。因此，在当前治疗中使用 FDA 批准的 PI3K 抑制剂可能潜在地改善 MLL 重排 ALL 患者的 GC 反应和预后。
