Ferroptosis-related molecular patterns reveal immune escape, inflammatory development and lipid metabolism characteristics of the tumor microenvironment in acute myeloid leukemia.
Ferroptosis-related molecular patterns reveal immune escape, inflammatory development and lipid metabolism characteristics of the tumor microenvironment in acute myeloid leukemia.
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铁死亡相关分子模式揭示急性髓系白血病肿瘤微环境的免疫逃逸、炎症发展和脂质代谢特征
DOI：
10.3389/fonc.2022.888570
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
越来越多的研究揭示了铁凋亡的影响因素。肿瘤微环境中免疫细胞浸润、炎症发展和脂质代谢对肿瘤细胞铁凋亡的影响有待进一步研究和探讨。我们从大样本分析和多组学的角度探讨了铁凋亡相关基因与急性髓细胞白血病（AML）的关系，采用多组鉴定和验证了铁凋亡相关分子模式，分析了不同分子模式组对铁凋亡的敏感性和免疫逃逸状态。单样本基因集富集分析（ssGSEA）算法被用来量化个体患者中的铁中毒相关分子模式的表型。用铁凋亡诱导剂RSL 3处理HL-60和THP-1细胞，以验证靶向抑制GPX 4的治疗价值。两种不同的测序方法发现了三种铁中毒相关的分子模式和进行性恶化的表型，包括免疫激活，免疫排斥和免疫抑制。我们构建的FS评分可以量化个体患者中铁中毒相关表型的发展。FS评分越高，患者预后越差。FS评分还与炎症发展、免疫逃逸、脂质代谢、免疫治疗耐药性和化疗耐药性等病理状况高度正相关，并与肿瘤突变负荷呈负相关。此外，RSL 3可通过降低GPX 4的蛋白水平诱导AML细胞的铁凋亡。本研究揭示了不同AML患者TME中免疫、炎症和脂质代谢的特点以及肿瘤细胞对铁凋亡敏感性的差异。FS评分可作为一种生物标志物，为临床评价AML患者的病理特征和设计个性化治疗方案提供参考。GPX 4是AML治疗的潜在靶点。
An increasing number of studies have revealed the influencing factors of ferroptosis. The influence of immune cell infiltration, inflammation development and lipid metabolism in the tumor microenvironment (TME) on the ferroptosis of tumor cells requires further research and discussion. We explored the relationship between ferroptosis-related genes and acute myeloid leukemia (AML) from the perspective of large sample analysis and multiomics, used multiple groups to identify and verify ferroptosis-related molecular patterns, and analyzed the sensitivity to ferroptosis and the state of immune escape between different molecular pattern groups. The single-sample gene set enrichment analysis (ssGSEA) algorithm was used to quantify the phenotypes of ferroptosis-related molecular patterns in individual patients. HL-60 and THP-1 cells were treated with ferroptosis inducer RSL3 to verify the therapeutic value of targeted inhibition of GPX4. Three ferroptosis-related molecular patterns and progressively worsening phenotypes including immune activation, immune exclusion and immunosuppression were found with the two different sequencing approaches. The FSscore we constructed can quantify the development of ferroptosis-related phenotypes in individual patients. The higher the FSscore is, the worse the patient’s prognosis. The FSscore is also highly positively correlated with pathological conditions such as inflammation development, immune escape, lipid metabolism, immunotherapy resistance, and chemotherapy resistance and is negatively correlated with tumor mutation burden. Moreover, RSL3 can induce ferroptosis of AML cells by reducing the protein level of GPX4. This study revealed the characteristics of immunity, inflammation, and lipid metabolism in the TME of different AML patients and differences in the sensitivity of tumor cells to ferroptosis. The FSscore can be used as a biomarker to provide a reference for the clinical evaluation of the pathological characteristics of AML patients and the design of personalized treatment plans. And GPX4 is a potential target for AML treatment.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
82.9
作者：
Bernard E;Nannya Y;Hasserjian RP;Devlin SM;Tuechler H;Medina-Martinez JS;Yoshizato T;Shiozawa Y;Saiki R;Malcovati L;Levine MF;Arango JE;Zhou Y;Solé F;Cargo CA;Haase D;Creignou M;Germing U;Zhang Y;Gundem G;Sarian A;van de Loosdrecht AA;Jädersten M;Tobiasson M;Kosmider O;Follo MY;Thol F;Pinheiro RF;Santini V;Kotsianidis I;Boultwood J;Santos FPS;Schanz J;Kasahara S;Ishikawa T;Tsurumi H;Takaori-Kondo A;Kiguchi T;Polprasert C;Bennett JM;Klimek VM;Savona MR;Belickova M;Ganster C;Palomo L;Sanz G;Ades L;Della Porta MG;Elias HK;Smith AG;Werner Y;Patel M;Viale A;Vanness K;Neuberg DS;Stevenson KE;Menghrajani K;Bolton KL;Fenaux P;Pellagatti A;Platzbecker U;Heuser M;Valent P;Chiba S;Miyazaki Y;Finelli C;Voso MT;Shih LY;Fontenay M;Jansen JH;Cervera J;Atsuta Y;Gattermann N;Ebert BL;Bejar R;Greenberg PL;Cazzola M;Hellström-Lindberg E;Ogawa S;Papaemmanuil E
通讯作者：
Papaemmanuil E
影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF