Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironment
Acute myeloid leukemia (AML) is one of the most aggressive hematological malignancies with a low 5-year survival rate and high rate of relapse. Developing more efficient therapies is an urgent need for AML treatment. Accumulating evidence showed that ferroptosis, an iron-dependent form of programmed...
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1207642/full |
| _version_ | 1797737554585321472 |
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| author | Denggang Fu Biyu Zhang Shiyong Wu Jueping Feng Hua Jiang |
| author_facet | Denggang Fu Biyu Zhang Shiyong Wu Jueping Feng Hua Jiang |
| author_sort | Denggang Fu |
| collection | DOAJ |
| description | Acute myeloid leukemia (AML) is one of the most aggressive hematological malignancies with a low 5-year survival rate and high rate of relapse. Developing more efficient therapies is an urgent need for AML treatment. Accumulating evidence showed that ferroptosis, an iron-dependent form of programmed cell death, is closely correlated with cancer initiation and clinical outcome through reshaping the tumor microenvironment. However, understanding of AML heterogeneity based on extensive profiling of ferroptosis signatures remains to be investigated yet. Herein, five independent AML transcriptomic datasets (TCGA-AML, GSE37642, GSE12417, GSE10358, and GSE106291) were obtained from the GEO and TCGA databases. Then, we identified two ferroptosis-related molecular subtypes (C1 and C2) with distinct prognosis and tumor immune microenvironment (TIME) by consensus clustering. Patients in the C1 subtype were associated with favorable clinical outcomes and increased cytotoxic immune cell infiltration, including CD8+/central memory T cells, natural killer (NK) cells, and non-regulatory CD4+ T cells while showing decreased suppressive immune subsets such as M2 macrophages, neutrophils, and monocytes. Functional enrichment analysis of differentially expressed genes (DEGs) implied that cell activation involved in immune response, leukocyte cell–cell adhesion and migration, and cytokine production were the main biological processes. Phagosome, antigen processing and presentation, cytokine–cytokine receptor interaction, B-cell receptor, and chemokine were identified as the major pathways. To seize the distinct landscape in C1 vs. C2 subtypes, a 5-gene prognostic signature (LSP1, IL1R2, MPO, CRIP1, and SLC24A3) was developed using LASSO Cox stepwise regression analysis and further validated in independent AML cohorts. Patients were divided into high- and low-risk groups, and decreased survival rates were observed in high- vs. low-risk groups. The TIME between high- and low-risk groups has a similar scenery in C1 vs. C2 subtypes. Single-cell-level analysis verified that LSP1 and CRIP1 were upregulated in AML and exhausted CD8+ T cells. Dual targeting of these two markers might present a promising immunotherapeutic for AML. In addition, potential effective chemical drugs for AML were predicted. Thus, we concluded that molecular subtyping using ferroptosis signatures could characterize the TIME and provide implications for monitoring clinical outcomes and predicting novel therapies. |
| first_indexed | 2024-03-12T13:30:24Z |
| format | Article |
| id | doaj.art-65db1383ed98467e8e88d47a84651632 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-12T13:30:24Z |
| publishDate | 2023-08-01 |
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| spelling | doaj.art-65db1383ed98467e8e88d47a846516322023-08-24T14:02:29ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-08-011110.3389/fcell.2023.12076421207642Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironmentDenggang Fu0Biyu Zhang1Shiyong Wu2Jueping Feng3Hua Jiang4College of Medicine, Medical University of South Carolina, Charleston, SC, United StatesSchool of Chemical Engineering and Pharmacy, Wuhan Institute of Technology Wuhan, Wuhan, ChinaDepartment of Pediatrics, The Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesWuhan Fourth Hospital, Wuhan, Hubei, ChinaDepartment of Radiation Oncology, School of Medicine, Stanford University, San Francisco, CA, United StatesAcute myeloid leukemia (AML) is one of the most aggressive hematological malignancies with a low 5-year survival rate and high rate of relapse. Developing more efficient therapies is an urgent need for AML treatment. Accumulating evidence showed that ferroptosis, an iron-dependent form of programmed cell death, is closely correlated with cancer initiation and clinical outcome through reshaping the tumor microenvironment. However, understanding of AML heterogeneity based on extensive profiling of ferroptosis signatures remains to be investigated yet. Herein, five independent AML transcriptomic datasets (TCGA-AML, GSE37642, GSE12417, GSE10358, and GSE106291) were obtained from the GEO and TCGA databases. Then, we identified two ferroptosis-related molecular subtypes (C1 and C2) with distinct prognosis and tumor immune microenvironment (TIME) by consensus clustering. Patients in the C1 subtype were associated with favorable clinical outcomes and increased cytotoxic immune cell infiltration, including CD8+/central memory T cells, natural killer (NK) cells, and non-regulatory CD4+ T cells while showing decreased suppressive immune subsets such as M2 macrophages, neutrophils, and monocytes. Functional enrichment analysis of differentially expressed genes (DEGs) implied that cell activation involved in immune response, leukocyte cell–cell adhesion and migration, and cytokine production were the main biological processes. Phagosome, antigen processing and presentation, cytokine–cytokine receptor interaction, B-cell receptor, and chemokine were identified as the major pathways. To seize the distinct landscape in C1 vs. C2 subtypes, a 5-gene prognostic signature (LSP1, IL1R2, MPO, CRIP1, and SLC24A3) was developed using LASSO Cox stepwise regression analysis and further validated in independent AML cohorts. Patients were divided into high- and low-risk groups, and decreased survival rates were observed in high- vs. low-risk groups. The TIME between high- and low-risk groups has a similar scenery in C1 vs. C2 subtypes. Single-cell-level analysis verified that LSP1 and CRIP1 were upregulated in AML and exhausted CD8+ T cells. Dual targeting of these two markers might present a promising immunotherapeutic for AML. In addition, potential effective chemical drugs for AML were predicted. Thus, we concluded that molecular subtyping using ferroptosis signatures could characterize the TIME and provide implications for monitoring clinical outcomes and predicting novel therapies.https://www.frontiersin.org/articles/10.3389/fcell.2023.1207642/fullacute myeloid leukemiaferroptosismolecule subtypingoutcomeimmune microenvironment |
| spellingShingle | Denggang Fu Biyu Zhang Shiyong Wu Jueping Feng Hua Jiang Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironment Frontiers in Cell and Developmental Biology acute myeloid leukemia ferroptosis molecule subtyping outcome immune microenvironment |
| title | Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironment |
| title_full | Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironment |
| title_fullStr | Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironment |
| title_full_unstemmed | Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironment |
| title_short | Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironment |
| title_sort | molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironment |
| topic | acute myeloid leukemia ferroptosis molecule subtyping outcome immune microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1207642/full |
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