NFATc1 as a therapeutic target in FLT3-ITD-positive AML
NFATc1 as a therapeutic target in FLT3-ITD-positive AML
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DOI：
10.1038/leu.2015.95
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发表时间：
2015-07-01
期刊：
影响因子：
11.4
通讯作者：
Burchert, A.
中科院分区：
文献类型：
--
作者：
Metzelder, S. K.;Michel, C.;Burchert, A.
FLT 3受体内部串联重复与急性髓细胞白血病预后不良相关FLT 3抑制剂如索拉非尼可能会改善预后，但只有少数患者表现出长期反应，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，我们发现活化T细胞的核因子NFATc 1在FLT 3-ITD阳性（FLT 3-ITD+）AML中经常过表达。使用诱导型短发夹RNA敲低NFATc 1或使用环孢素A（CsA）或VIVIT进行药理学NFAT抑制可显著增强索拉非尼诱导的FLT 3-ITD+细胞凋亡。CsA还有效地克服了FLT 3-ITD+细胞系和原发性AML中的索拉非尼耐药性。反之亦然，组成型核NFATc 1突变体的从头表达介导了体外即时和稳健的索拉非尼耐药性。有趣的是，与野生型FLT 3（FLT 3-WT）AML患者相比，接受CsA作为补救化疗一部分的FLT 3-ITD+ AML患者（n = 26）显示出上级结局。我们的数据揭示了NFATc 1作为FLT 3-ITD+ AML中索拉非尼耐药的新介质。CsA抵消索拉非尼耐药性，并可能通过抑制NFAT改善AML的治疗结果。
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.