Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value.
Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value.
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急性髓系白血病 VISTA 的综合转录组分析：深入了解其预后价值。
DOI：
10.3390/ijms232314885
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发表时间：
2022-11-28
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
t细胞活化的v域Ig抑制因子（VISTA）已被认为是抗肿瘤免疫反应的关键负调控因子，并且作为免疫治疗的潜在药理学靶点越来越受到关注。该分子在造血干细胞和髓系细胞中高度表达，在急性髓系白血病（AML）中被发现表达上调。然而，在髓系恶性肿瘤中，vista相关的免疫特征相对未被探索。在此，我们旨在探索这种免疫检查点调节剂是否在AML患者免疫逃逸环境的产生中发挥作用。通过大规模和单细胞RNA测序，我们在白血病细胞系和大量公开的健康个体和AML患者骨髓标本中表征了VISTA mRNA的表达水平。我们还使用疾病发病时AML样本的全外显子组测序结果定义了与白血病相关负担的相关性。我们发现，在正常造血过程中，VISTA的表达在骨髓分化树中呈线性增加。因此，在AML细胞系以及诊断为骨髓单核细胞和单核细胞分化的AML患者中，其转录物高度富集。与FLT3病变的存在无关，NPM1突变与FLT3病变有很强的相关性。此外，在核型正常且NPM1突变的患者中，VISTA的基线表达水平与疾病复发相关，根据目前的诊断方案，这一亚组传统上被认为是有利的。事实上，与长期缓解的患者（标准化疗方案后5年）相比，诊断后2年内复发的患者在白血病和T细胞中的VISTA表达均增加。我们的研究结果为开发以vista为目标的治疗策略来治疗分子定义的AML患者亚群以预防疾病复发和治疗耐药性提供了理论依据。
The V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid compartment, and it has been found upmodulated in acute myeloid leukemia (AML). However, VISTA-associated immune features are relatively unexplored in myeloid malignancies. Herein, we aimed to explore whether this immune checkpoint regulator could play a role in the generation of an immune escape environment in AML patients. We characterized VISTA mRNA expression levels in leukemia cell lines and in large publicly available cohorts of specimens from bone marrow of healthy individuals and AML patients at diagnosis by deploying bulk and single-cell RNA sequencing. We also defined the correlations with leukemia-associated burden using results of whole-exome sequencing of AML samples at disease onset. We showed that VISTA expression linearly increased across the myeloid differentiation tree in normal hematopoiesis. Accordingly, its transcript was highly enriched in AML cell lines as well as in AML patients at diagnosis presenting with myelomonocytic and monocytic differentiation. A strong correlation was seen with NPM1 mutations regardless of the presence of FLT3 lesions. Furthermore, VISTA expression levels at baseline correlated with disease recurrence in patients with normal karyotype and NPM1 mutations, a subgroup traditionally considered as favorable according to current diagnostic schemes. Indeed, when compared to patients with long-term remission (>5 years after standard chemotherapy regimens), cases relapsing within 2 years from diagnosis had increased VISTA expression in both leukemia and T cells. Our results suggest a rationale for developing VISTA-targeted therapeutic strategies to treat molecularly defined subgroups of AML patients to prevent disease recurrence and treatment resistance.
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影响因子：
64.8
作者：
Tyner JW;Tognon CE;Bottomly D;Wilmot B;Kurtz SE;Savage SL;Long N;Schultz AR;Traer E;Abel M;Agarwal A;Blucher A;Borate U;Bryant J;Burke R;Carlos A;Carpenter R;Carroll J;Chang BH;Coblentz C;d'Almeida A;Cook R;Danilov A;Dao KT;Degnin M;Devine D;Dibb J;Edwards DK 5th;Eide CA;English I;Glover J;Henson R;Ho H;Jemal A;Johnson K;Johnson R;Junio B;Kaempf A;Leonard J;Lin C;Liu SQ;Lo P;Loriaux MM;Luty S;Macey T;MacManiman J;Martinez J;Mori M;Nelson D;Nichols C;Peters J;Ramsdill J;Rofelty A;Schuff R;Searles R;Segerdell E;Smith RL;Spurgeon SE;Sweeney T;Thapa A;Visser C;Wagner J;Watanabe-Smith K;Werth K;Wolf J;White L;Yates A;Zhang H;Cogle CR;Collins RH;Connolly DC;Deininger MW;Drusbosky L;Hourigan CS;Jordan CT;Kropf P;Lin TL;Martinez ME;Medeiros BC;Pallapati RR;Pollyea DA;Swords RT;Watts JM;Weir SJ;Wiest DL;Winters RM;McWeeney SK;Druker BJ
通讯作者：
Druker BJ
影响因子：
11.2
作者：
Le Mercier I;Chen W;Lines JL;Day M;Li J;Sergent P;Noelle RJ;Wang L
通讯作者：
Wang L
DOI：
10.1084/jem.20100619
发表时间：
2011-03-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Wang L;Rubinstein R;Lines JL;Wasiuk A;Ahonen C;Guo Y;Lu LF;Gondek D;Wang Y;Fava RA;Fiser A;Almo S;Noelle RJ
通讯作者：
Noelle RJ
影响因子：
10.1
作者：
Xu, Wenwen;Dong, Juan;Wang, Li
通讯作者：
Wang, Li
影响因子：
50.3
作者：
Dufva, Olli;Polonen, Petri;Mustjoki, Satu
通讯作者：
Mustjoki, Satu