Indoleamine 2, 3-Dioxygenase 1 Mediates Survival Signals in Chronic Lymphocytic Leukemia via Kynurenine/Aryl Hydrocarbon Receptor-Mediated MCL1 Modulation.
Indoleamine 2, 3-Dioxygenase 1 Mediates Survival Signals in Chronic Lymphocytic Leukemia via Kynurenine/Aryl Hydrocarbon Receptor-Mediated MCL1 Modulation.
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吲哚胺 2, 3-双加氧酶 1 通过犬尿氨酸/芳基烃受体介导的 MCL1 调节介导慢性淋巴细胞白血病的生存信号。
DOI：
10.3389/fimmu.2022.832263
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发表时间：
2022
影响因子：
7.3
通讯作者：
Marasca R
中科院分区：
文献类型：
--
作者：
Atene CG;Fiorcari S;Mesini N;Alboni S;Martinelli S;Maccaferri M;Leonardi G;Potenza L;Luppi M;Maffei R;Marasca R
吲哚胺2，3-双加氧酶1（IDO 1）代谢回路，包括第一色氨酸（Trp）分解代谢产物L-犬尿氨酸（Kyn）和芳烃受体（AHR），已成为癌症免疫逃避的机制。在这里，我们研究了IDO 1/Kyn/AHR轴在慢性淋巴细胞白血病（CLL）中的功能作用。我们的数据表明，CLL细胞表达IDO 1酶的活性形式，微环境刺激可以积极调节其表达。干扰素（IFN）-γ通过Jak/STAT 1途径诱导IDO 1表达，并介导Kyn产生，同时在CLL条件培养基中消耗Trp，而INCB 018424（ruxolitinib），一种JAK 1/2抑制剂，削弱了这两种作用。为了表征IDO 1参与白血病细胞维持的特征，我们通过载体转染过表达IDO 1，测量对自发性细胞凋亡的增强抗性。IDO 1促存活影响通过用Kyn处理CLL细胞来证实，Kyn介导诱导的髓性白血病细胞分化蛋白（MCL 1）的增加。相反，通过CH-223191沉默或阻断AHR可改善白血病克隆的细胞凋亡并减轻MCL 1的表达。此外，Kyn处理的CLL细胞受ABT-199（维奈托克）促凋亡作用的影响较小，而CH-223191显示出与该药物的协同/累加细胞毒性。最后，用AMG-176直接靶向CLL细胞中的MCL 1，我们消除了Kyn的促存活作用。总之，我们的数据确定IDO 1/Kyn/AHR信号传导作为CLL的新治疗靶点，首次描述了其在CLL病理生物学中的作用。
The indoleamine 2,3-dioxygenase 1 (IDO1) metabolic circuitry, comprising the first tryptophan (Trp) catabolite L-kynurenine (Kyn) and the aryl hydrocarbon receptor (AHR), has emerged as a mechanism of cancer immune evasion. Here, we investigated the functional role of the IDO1/Kyn/AHR axis in chronic lymphocytic leukemia (CLL). Our data show that CLL cells expressed an active form of the IDO1 enzyme and microenvironmental stimuli can positively modulate its expression. Interferon (IFN)-γ induces IDO1 expression through the Jak/STAT1 pathway and mediates Kyn production concomitantly with Trp consumption in CLL-conditioned media, while INCB018424 (ruxolitinib), a JAK1/2 inhibitor, impaired both effects. To characterize the involvement of IDO1 in leukemic cell maintenance, we overexpressed IDO1 by vector transfection measuring enhanced resistance to spontaneous apoptosis. IDO1 pro-survival influence was confirmed by treating CLL cells with Kyn, which mediated the increase of induced myeloid leukemia cell differentiation protein (MCL1). Conversely, AHR silencing or its blockade via CH-223191 improved the apoptosis of leukemic clones and mitigated MCL1 expression. Moreover, Kyn-treated CLL cells are less affected by the pro-apoptotic effect of ABT-199 (venetoclax), while CH-223191 showed synergistic/additive cytotoxicity with this drug. Lastly, targeting directly MCL1 in CLL cells with AMG-176, we abrogate the pro-survival effect of Kyn. In conclusion, our data identify IDO1/Kyn/AHR signaling as a new therapeutic target for CLL, describing for the first time its role in CLL pathobiology.
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DOI：
10.1016/j.bbi.2017.05.006
发表时间：
2017-10
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Borsini A;Alboni S;Horowitz MA;Tojo LM;Cannazza G;Su KP;Pariante CM;Zunszain PA
通讯作者：
Zunszain PA
DOI：
10.1200/jco.20.00948
发表时间：
2020-12-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
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通讯作者：
Seymour JF
影响因子：
20.3
作者：
Jitschin, Regina;Braun, Martina;Mougiakakos, Dimitrios
通讯作者：
Mougiakakos, Dimitrios
影响因子：
2.7
作者：
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通讯作者：
Quesnel, Bruno
影响因子：
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作者：
Liu Y;Zhang Y;Zheng X;Zhang X;Wang H;Li Q;Yuan K;Zhou N;Yu Y;Song N;Fu J;Min W
通讯作者：
Min W