Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia
Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia
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DOI：
10.1111/ejh.13183
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发表时间：
2019-02-01
影响因子：
3.1
通讯作者：
Recher, Christian
中科院分区：
文献类型：
--
作者：
Bertoli, Sarah;Paubelle, Etienne;Recher, Christian
目的我们先前报道了血清铁蛋白在中危急性髓系白血病(AML)患者中的预后价值。这项研究的目的是在更大的队列中证实这一发现，而不考虑年龄和预后亚组，探索铁蛋白在AML细胞中的表达和功能作用，以及AML患者血清铁蛋白水平的调节。患者/材料/方法收集了525名接受强化化疗的患者在确诊时的血清铁蛋白水平。在硅胶、体外和体内分析评估FTH1和FTL在AML中的表达模式和功能作用。结果证实了血清铁蛋白对预后的独立预测价值。在转录数据库中，与正常造血干细胞相比，FTH1和FTL在AML和白血病干细胞中过表达。从AML患者设计的过度表达FTH1的基因签名显示，免疫和炎症反应的基因显著丰富，包括核因子-KB途径、氧化应激或铁途径。在患者来源的异种移植模型中，这种基因特征在对阿糖胞苷耐药的AML细胞中得到了丰富。FTH1蛋白在患者样本中也有过表达，并与阿糖胞苷的体外细胞毒活性相关。最后，我们证明了化疗引起了炎症反应，包括在诱导化疗的第1天到第8天，血清铁蛋白水平显著升高，地塞米松阻断了这一反应。结论铁蛋白在大多数AML患者中表达异常，可能通过炎症反应，与化疗耐药有关，可能成为新的治疗靶点。
Objectives We previously reported the prognostic value of serum ferritin in younger patients with intermediate-risk acute myeloid leukemia (AML). The aims of this study were to confirm this finding in a larger cohort regardless of age and prognostic subgroups, to explore the expression and functional role of ferritin in AML cells as well as the regulation of serum ferritin levels in AML patients. Patients/Materials/Methods Serum ferritin levels at diagnosis were collected in a cohort of 525 patients treated by intensive chemotherapy. In silico, in vitro, and in vivo analyses were conducted to assess the pattern of expression and functional role of FTH1 and FTL in AML. Results We confirmed the independent prognostic value of serum ferritin. In transcriptomic databases, FTH1 and FTL were overexpressed in AML and leukemic stem cells compared to normal hematopoietic stem cells. The gene signature designed from AML patients overexpressing FTH1 revealed a significant enrichment in genes of the immune and inflammatory response including Nf-KB pathway, oxidative stress, or iron pathways. This gene signature was enriched in cytarabine-resistant AML cells in a patient-derived xenograft model. FTH1 protein was also overexpressed in patient's samples and correlated with the in vitro cytotoxic activity of cytarabine. Lastly, we demonstrated that chemotherapy induced an inflammatory response including a significant increase in serum ferritin levels between day 1 and 8 of induction chemotherapy that was blocked by dexamethasone. Conclusion Ferritin is deregulated in most AML patients likely through inflammation, associated with chemoresistance, and could represent a new therapeutic target.