FLT3-ITD promotes immune checkpoint CD80 via ROS elevation in acute myeloid leukemia
Acute myeloid leukemia (AML), a malignant hematological stem cell disease, arises from the malignant transformation of myeloid progenitor cells. Among the genetic aberrations in AML, mutations in the tyrosine kinase receptor FLT3, especially FLT3-ITD, are most frequently detected and are correlated...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1577313/full |
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| author | Libo Yan Weiming Zhang Qiyan Mo Daogang Wang Ning Xu Mengzhe Yang Tao Ren |
| author_facet | Libo Yan Weiming Zhang Qiyan Mo Daogang Wang Ning Xu Mengzhe Yang Tao Ren |
| author_sort | Libo Yan |
| collection | DOAJ |
| description | Acute myeloid leukemia (AML), a malignant hematological stem cell disease, arises from the malignant transformation of myeloid progenitor cells. Among the genetic aberrations in AML, mutations in the tyrosine kinase receptor FLT3, especially FLT3-ITD, are most frequently detected and are correlated with poor clinical outcomes. Intriguingly, FLT3-ITD is implicated in immune escape, although the underlying mechanism remains elusive. The present study aims to elucidate the relationship between FLT3-ITD and the immune checkpoint molecule CD80, which is crucial for immune regulation. Our results provide compelling evidence that a moderate level of CD80 localizes on the cell surface of FLT3-ITD AML cells. Mechanistically, FLT3-ITD upregulates CD80 expression by increasing intracellular reactive oxygen species (ROS) levels and subsequent CD80 enhancement. Significantly, we found that treatment with a HIF-1α inhibitor selectively suppressed the proliferation of FLT3-ITD-positive leukemic cells and induced excessive ROS production, which consequently led to CD80 overexpression. Collectively, our findings unravel the molecular pathway through which FLT3-ITD augments CD80 expression via ROS, suggesting a potential immune evasion. Moreover, this study points to a novel therapeutic strategy that combines chemotherapy-induced CD80 overexpression with immune checkpoint-targeted immunotherapy to eradicate FLT3-ITD AML cells. |
| format | Article |
| id | doaj-art-d8372535a69f412db80541ace77f0cfa |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-d8372535a69f412db80541ace77f0cfa2025-08-20T03:13:21ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.15773131577313FLT3-ITD promotes immune checkpoint CD80 via ROS elevation in acute myeloid leukemiaLibo Yan0Weiming Zhang1Qiyan Mo2Daogang Wang3Ning Xu4Mengzhe Yang5Tao Ren6Xianning Medical College, Hubei University of Science and Technology, Xianning, ChinaDepartment of Oncology, Wuming Hospital of Guangxi Medical University, Nanning, ChinaDepartment of Oncology, Wuming Hospital of Guangxi Medical University, Nanning, ChinaDepartment of Clinical Medicine, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, ChinaDepartment of Clinical Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, ChinaDepartment of Scientific Research, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaDepartment of Oncology, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, ChinaAcute myeloid leukemia (AML), a malignant hematological stem cell disease, arises from the malignant transformation of myeloid progenitor cells. Among the genetic aberrations in AML, mutations in the tyrosine kinase receptor FLT3, especially FLT3-ITD, are most frequently detected and are correlated with poor clinical outcomes. Intriguingly, FLT3-ITD is implicated in immune escape, although the underlying mechanism remains elusive. The present study aims to elucidate the relationship between FLT3-ITD and the immune checkpoint molecule CD80, which is crucial for immune regulation. Our results provide compelling evidence that a moderate level of CD80 localizes on the cell surface of FLT3-ITD AML cells. Mechanistically, FLT3-ITD upregulates CD80 expression by increasing intracellular reactive oxygen species (ROS) levels and subsequent CD80 enhancement. Significantly, we found that treatment with a HIF-1α inhibitor selectively suppressed the proliferation of FLT3-ITD-positive leukemic cells and induced excessive ROS production, which consequently led to CD80 overexpression. Collectively, our findings unravel the molecular pathway through which FLT3-ITD augments CD80 expression via ROS, suggesting a potential immune evasion. Moreover, this study points to a novel therapeutic strategy that combines chemotherapy-induced CD80 overexpression with immune checkpoint-targeted immunotherapy to eradicate FLT3-ITD AML cells.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1577313/fullimmune checkpointCD80ROSFLT3-ITDleukemia |
| spellingShingle | Libo Yan Weiming Zhang Qiyan Mo Daogang Wang Ning Xu Mengzhe Yang Tao Ren FLT3-ITD promotes immune checkpoint CD80 via ROS elevation in acute myeloid leukemia Frontiers in Immunology immune checkpoint CD80 ROS FLT3-ITD leukemia |
| title | FLT3-ITD promotes immune checkpoint CD80 via ROS elevation in acute myeloid leukemia |
| title_full | FLT3-ITD promotes immune checkpoint CD80 via ROS elevation in acute myeloid leukemia |
| title_fullStr | FLT3-ITD promotes immune checkpoint CD80 via ROS elevation in acute myeloid leukemia |
| title_full_unstemmed | FLT3-ITD promotes immune checkpoint CD80 via ROS elevation in acute myeloid leukemia |
| title_short | FLT3-ITD promotes immune checkpoint CD80 via ROS elevation in acute myeloid leukemia |
| title_sort | flt3 itd promotes immune checkpoint cd80 via ros elevation in acute myeloid leukemia |
| topic | immune checkpoint CD80 ROS FLT3-ITD leukemia |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1577313/full |
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