Midostaurin reduces Regulatory T cells markers in Acute Myeloid Leukemia.
Midostaurin reduces Regulatory T cells markers in Acute Myeloid Leukemia.
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DOI：
10.1038/s41598-018-35978-0
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发表时间：
2018-12-03
影响因子：
4.6
通讯作者：
Alachkar H
中科院分区：
文献类型：
--
作者：
Gutierrez L;Jang M;Zhang T;Akhtari M;Alachkar H
急性髓系白血病（AML）是一种异质性血液恶性肿瘤，其中唯一的治愈方法是异基因干细胞移植（Allo - HSCT）。供体T细胞对白血病克隆的识别和清除对异基因干细胞移植的成功有重要贡献。FLT3 - ITD是AML中一种常见的突变，与不良预后相关。最近，米哚妥林成为首个被美国食品药品监督管理局（FDA）批准用于移植前伴有FLT3 - ITD的患者且与标准疗法联合使用的FLT3抑制剂。除了其可能影响T细胞信号传导的多激酶活性外，FLT3抑制剂还诱导恶性细胞凋亡，这也可能增强抗原呈递以激活T细胞。考虑到这些抑制剂在AML患者中的临床使用增加，以及作为单一药物使用时所产生的临床益处有限，需要了解FLT3抑制剂如何影响T细胞群及其功能以提高其临床益处。我们研究了四种不同的FLT3抑制剂（米哚妥林、索拉非尼、坦度替尼和奎扎替尼）对从健康供体和AML患者获取的外周血单个核细胞（PBMC）中T细胞群的影响。米哚妥林使健康人和AML患者的外周血单个核细胞中CD4 + CD25 + FOXP3 + T细胞群以及FOXP3 mRNA表达显著降低。同样，从接受米哚妥林治疗的AML患者采集的样本显示调节性T细胞（Tregs）标志物减少。在米哚妥林治疗后，干扰素 - γ（IFN - γ）、肿瘤坏死因子 - α（TNF - α）和白细胞介素 - 10（IL - 10）水平也降低。考虑到美国食品药品监督管理局批准米哚妥林用于移植前的AML患者，我们的发现将具有重要的临床意义，因为它为在移植后患者中使用米哚妥林进行功能研究提供了理论依据。
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy in which the only curative approach is allogeneic stem cell transplant (Allo-HSCT). The recognition and elimination of leukemic clones by donor T-cells contribute significantly to Allo-HSCT success. FLT3-ITD, a common mutation in AML, is associated with poor prognosis. Recently, midostaurin became the first FDA approved FLT3-inhibitor for pre-transplant patients with FLT3-ITD in combination with standard therapy. In addition to their multikinase activity which may affect T-cell signaling, FLT3-inhibitors induce apoptosis of malignant cells which may also enhance antigen presentation to activate T-cells. Considering the increased clinical use of these inhibitors in patients with AML, and the limited clinical benefit derived from their use as single agents, understanding how FLT3-inhibitors affect T cell population and function is needed to improve their clinical benefit. We examined the effect of four different FLT3 inhibitors (midostaurin, sorafenib, tandutinib, and quizartenib) on T cell populations in peripheral blood mononuclear cells (PBMC) obtained from healthy donors and from patients with AML. Midostaurin exhibited a significant decrease in CD4 + CD25 + FOXP3+ T cell population and FOXP3 mRNA expression in healthy and AML PBMCs. Similarly, samples collected from patients with AML treated with midostaurin showed a reduction in Tregs markers. Interferon-γ(IFN-γ), tumor necrosis factor-α(TNF-α), and IL-10 levels were also reduced following midostaurin treatment. Considering the FDA approval of midostaurin for use in patients with AML in the pre-transplant setting, our finding will have important clinical implication as it provides the rationale for functional investigation of the use of midostaurin in post-transplant patients.
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影响因子：
11.4
作者：
Reiter K;Polzer H;Krupka C;Maiser A;Vick B;Rothenberg-Thurley M;Metzeler KH;Dörfel D;Salih HR;Jung G;Nößner E;Jeremias I;Hiddemann W;Leonhardt H;Spiekermann K;Subklewe M;Greif PA
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Greif PA
影响因子：
4.4
作者：
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通讯作者：
Farrar, Michael A.
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Simonetta F;Gestermann N;Martinet KZ;Boniotto M;Tissières P;Seddon B;Bourgeois C
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Bourgeois C
影响因子：
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作者：
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通讯作者：
Linch, DC
影响因子：
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作者：
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通讯作者：
Roberts, D. J.