Department of Pediatric Oncology/Haematology, Erasmus Medical Center/Sophia Children's Hospital, Dr Molewaterplein 50, Rotterdam, The Netherlands.
Leukemia. 2013 Apr;27(5):1063-71. doi: 10.1038/leu.2012.372. Epub 2012 Dec 28.
MLL-rearranged infant acute lymphoblastic leukemia (ALL) (<1 year of age) are frequently resistant to glucocorticoids, like prednisone and dexamethasone. As poor glucocorticoid responses are strongly associated with therapy failure, overcoming glucocorticoid resistance may be a crucial step towards improving prognosis. Unfortunately, the mechanisms underlying glucocorticoid resistance in MLL-rearranged ALL largely remain obscure. We here defined a gene signature that accurately discriminates between prednisolone-resistant and prednisolone-sensitive MLL-rearranged infant ALL patient samples, demonstrating that, among other genes, high-level ANXA2 is associated with prednisolone resistance in this type of leukemia. Further investigation demonstrated that the underlying factor of this association was the presence of Src kinase-induced phosphorylation (activation) of annexin A2, a process requiring the adapter protein p11 (encoded by human S100A10). shRNA-mediated knockdown of either ANXA2, FYN, LCK or S100A10, all led to inhibition of annexin A2 phosphorylation and resulted in marked sensitization to prednisolone. Likewise, exposure of prednisolone-resistant MLL-rearranged ALL cells to different Src kinase inhibitors exerting high specificity towards FYN and/or LCK had similar effects. In conclusion, we here present a novel mechanism of prednisolone resistance in MLL-rearranged leukemias, and propose that inhibition of annexin A2 phosphorylation embodies a therapeutic strategy for overcoming resistance to glucocorticoids in this highly aggressive type of leukemia.
MLL 重排婴儿急性淋巴细胞白血病（ALL）（<1 岁）常对糖皮质激素（如泼尼松和地塞米松）耐药。由于糖皮质激素反应不良与治疗失败密切相关，克服糖皮质激素耐药性可能是改善预后的关键步骤。不幸的是，MLL 重排 ALL 中糖皮质激素耐药的机制在很大程度上仍然不清楚。我们在这里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，表明在其他基因中，高水平的 ANXA2 与这种类型白血病中的泼尼松耐药有关。进一步的研究表明，这种关联的基础因素是Src 激酶诱导的膜联蛋白 A2 磷酸化（激活），这一过程需要衔接蛋白 p11（由人类 S100A10 编码）。shRNA 介导的 ANXA2、FYN、LCK 或 S100A10 的敲低均导致膜联蛋白 A2 磷酸化的抑制，并导致对泼尼松的显著增敏。同样，将泼尼松耐药的 MLL 重排 ALL 细胞暴露于不同的 Src 激酶抑制剂中，这些抑制剂对 FYN 和/或 LCK 具有高度特异性，也具有类似的效果。总之，我们在这里提出了 MLL 重排白血病中泼尼松耐药的一种新机制，并提出抑制膜联蛋白 A2 磷酸化是克服这种高度侵袭性白血病对糖皮质激素耐药性的一种治疗策略。
