A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia
Abstract Background t(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities in acute myeloid leukemia (AML), leading to the generation of the fusion protein AML1-ETO. Despite t(8;21) AML being considered as a subtype with a favorable prognosis, approximately 30–50% of patients experie...
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Experimental Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40164-024-00480-z |
| _version_ | 1797276686211874816 |
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| author | Wei Zhou Siying Li Hong Wang Jingfeng Zhou Shuyi Li Guofeng Chen Wei Guan Xianli Fu Clara Nervi Li Yu Yonghui Li |
| author_facet | Wei Zhou Siying Li Hong Wang Jingfeng Zhou Shuyi Li Guofeng Chen Wei Guan Xianli Fu Clara Nervi Li Yu Yonghui Li |
| author_sort | Wei Zhou |
| collection | DOAJ |
| description | Abstract Background t(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities in acute myeloid leukemia (AML), leading to the generation of the fusion protein AML1-ETO. Despite t(8;21) AML being considered as a subtype with a favorable prognosis, approximately 30–50% of patients experience drug resistance and subsequent relapse. N6-methyladenosine (m6A) is demonstrated to be involved in the development of AML. However, the regulatory mechanisms between AML1-ETO and m6A-related enzymes and the roles of dysregulated m6A modifications in the t(8;21)-leukemogenesis and chemoresistance remain elusive. Methods Chromatin immunoprecipitation, dual-luciferase reporter assay, m6A-qPCR, RNA immunoprecipitation, and RNA stability assay were used to investigate a regulatory loop between AML1-ETO and FTO, an m6A demethylase. Gain- and loss-of-function experiments both in vitro and in vivo were further performed. Transcriptome-wide RNA sequencing and m6A sequencing were conducted to identify the potential targets of FTO. Results Here we show that FTO is highly expressed in t(8;21) AML, especially in patients with primary refractory disease. The expression of FTO is positively correlated with AML1-ETO, which is attributed to a positive regulatory loop between the AML1-ETO and FTO. Mechanistically, AML1-ETO upregulates FTO expression through inhibiting the transcriptional repression of FTO mediated by PU.1. Meanwhile, FTO promotes the expression of AML1-ETO by inhibiting YTHDF2-mediated AML1-ETO mRNA decay. Inactivation of FTO significantly suppresses cell proliferation, promotes cell differentiation and renders resistant t(8;21) AML cells sensitive to Ara-C. FTO exerts functions by regulating its mRNA targets, especially IGFBP2, in an m6A-dependent manner. Regain of Ara-C tolerance is observed when IGFBP2 is overexpressed in FTO-knockdown t(8;21) AML cells. Conclusion Our work reveals a therapeutic potential of targeting AML1-ETO/FTO/IGFBP2 minicircuitry in the treatment for t(8;21) patients with resistance to Ara-C. |
| first_indexed | 2024-03-07T15:31:47Z |
| format | Article |
| id | doaj.art-7ed03736c5a44f6cb0e35573976dddab |
| institution | Directory Open Access Journal |
| issn | 2162-3619 |
| language | English |
| last_indexed | 2024-03-07T15:31:47Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj.art-7ed03736c5a44f6cb0e35573976dddab2024-03-05T16:22:08ZengBMCExperimental Hematology & Oncology2162-36192024-01-0113112410.1186/s40164-024-00480-zA novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemiaWei Zhou0Siying Li1Hong Wang2Jingfeng Zhou3Shuyi Li4Guofeng Chen5Wei Guan6Xianli Fu7Clara Nervi8Li Yu9Yonghui Li10Central Laboratory, Shenzhen University General Hospital, Shenzhen UniversitySchool of Medicine, South China University of TechnologyCentral Laboratory, Shenzhen University General Hospital, Shenzhen UniversityDepartment of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen UniversityDepartment of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen UniversityDepartment of Endoscopy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for CancerSenior Department of Hematology, The Fifth Medical Center of PLA General HospitalDepartment of Pathology, Shenzhen University General HospitalDepartment of Medical and Surgical Sciences and Biotechnologies, University of Roma La SapienzaDepartment of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen UniversityCentral Laboratory, Shenzhen University General Hospital, Shenzhen UniversityAbstract Background t(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities in acute myeloid leukemia (AML), leading to the generation of the fusion protein AML1-ETO. Despite t(8;21) AML being considered as a subtype with a favorable prognosis, approximately 30–50% of patients experience drug resistance and subsequent relapse. N6-methyladenosine (m6A) is demonstrated to be involved in the development of AML. However, the regulatory mechanisms between AML1-ETO and m6A-related enzymes and the roles of dysregulated m6A modifications in the t(8;21)-leukemogenesis and chemoresistance remain elusive. Methods Chromatin immunoprecipitation, dual-luciferase reporter assay, m6A-qPCR, RNA immunoprecipitation, and RNA stability assay were used to investigate a regulatory loop between AML1-ETO and FTO, an m6A demethylase. Gain- and loss-of-function experiments both in vitro and in vivo were further performed. Transcriptome-wide RNA sequencing and m6A sequencing were conducted to identify the potential targets of FTO. Results Here we show that FTO is highly expressed in t(8;21) AML, especially in patients with primary refractory disease. The expression of FTO is positively correlated with AML1-ETO, which is attributed to a positive regulatory loop between the AML1-ETO and FTO. Mechanistically, AML1-ETO upregulates FTO expression through inhibiting the transcriptional repression of FTO mediated by PU.1. Meanwhile, FTO promotes the expression of AML1-ETO by inhibiting YTHDF2-mediated AML1-ETO mRNA decay. Inactivation of FTO significantly suppresses cell proliferation, promotes cell differentiation and renders resistant t(8;21) AML cells sensitive to Ara-C. FTO exerts functions by regulating its mRNA targets, especially IGFBP2, in an m6A-dependent manner. Regain of Ara-C tolerance is observed when IGFBP2 is overexpressed in FTO-knockdown t(8;21) AML cells. Conclusion Our work reveals a therapeutic potential of targeting AML1-ETO/FTO/IGFBP2 minicircuitry in the treatment for t(8;21) patients with resistance to Ara-C.https://doi.org/10.1186/s40164-024-00480-zt(8;21) acute myeloid leukemiaAML1-ETON6-methyladenosineFTOAra-C resistance |
| spellingShingle | Wei Zhou Siying Li Hong Wang Jingfeng Zhou Shuyi Li Guofeng Chen Wei Guan Xianli Fu Clara Nervi Li Yu Yonghui Li A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia Experimental Hematology & Oncology t(8;21) acute myeloid leukemia AML1-ETO N6-methyladenosine FTO Ara-C resistance |
| title | A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia |
| title_full | A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia |
| title_fullStr | A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia |
| title_full_unstemmed | A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia |
| title_short | A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia |
| title_sort | novel aml1 eto fto positive feedback loop promotes leukemogenesis and ara c resistance via stabilizing igfbp2 in t 8 21 acute myeloid leukemia |
| topic | t(8;21) acute myeloid leukemia AML1-ETO N6-methyladenosine FTO Ara-C resistance |
| url | https://doi.org/10.1186/s40164-024-00480-z |
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