Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
Universitätsklinikum Carl-Gustav-Carus, Technische Universität Dresden, Fetscherstraße Dresden, Germany.
Leukemia. 2015 Jul;29(7):1470-7. doi: 10.1038/leu.2015.95. Epub 2015 Apr 14.
Internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) are associated with a dismal prognosis in acute myeloid leukemia (AML). FLT3 inhibitors such as sorafenib may improve outcome, but only few patients display long-term responses, prompting the search for underlying resistance mechanisms and therapeutic strategies to overcome them. Here we identified that the nuclear factor of activated T cells, NFATc1, is frequently overexpressed in FLT3-ITD-positive (FLT3-ITD+) AML. NFATc1 knockdown using inducible short hairpin RNA or pharmacological NFAT inhibition with cyclosporine A (CsA) or VIVIT significantly augmented sorafenib-induced apoptosis of FLT3-ITD+ cells. CsA also potently overcame sorafenib resistance in FLT3-ITD+ cell lines and primary AML. Vice versa, de novo expression of a constitutively nuclear NFATc1-mutant mediated instant and robust sorafenib resistance in vitro. Intriguingly, FLT3-ITD+ AML patients (n=26) who received CsA as part of their rescue chemotherapy displayed a superior outcome when compared with wild-type FLT3 (FLT3-WT) AML patients. Our data unveil NFATc1 as a novel mediator of sorafenib resistance in FLT3-ITD+ AML. CsA counteracts sorafenib resistance and may improve treatment outcome in AML by means of inhibiting NFAT.
内部串联重复（ITD）在 Fms 相关酪氨酸激酶 3 受体（FLT3）中与急性髓系白血病（AML）的不良预后相关。FLT3 抑制剂，如索拉非尼，可能改善预后，但只有少数患者显示出长期反应，这促使人们寻找潜在的耐药机制和治疗策略来克服它们。在这里，我们发现激活 T 细胞的核因子 NFATc1 在 FLT3-ITD 阳性（FLT3-ITD+）AML 中经常过表达。使用诱导性短发夹 RNA 或环孢素 A（CsA）或 VIVIT 进行药理学 NFAT 抑制，可显著增强 FLT3-ITD+细胞中索拉非尼诱导的细胞凋亡。CsA 还能有效地克服 FLT3-ITD+细胞系和原发性 AML 中的索拉非尼耐药性。相反，组成型核 NFATc1 突变体的从头表达在体外即刻和强烈地介导了索拉非尼耐药性。有趣的是，接受 CsA 作为其挽救化疗一部分的 FLT3-ITD+ AML 患者（n=26）与野生型 FLT3（FLT3-WT）AML 患者相比，显示出更好的结果。我们的数据揭示了 NFATc1 是 FLT3-ITD+ AML 中索拉非尼耐药的一种新型介质。CsA 可抵抗索拉非尼耐药性，并通过抑制 NFAT 改善 AML 的治疗结果。
