Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates HOXA9 Gene Expression in t(4;11) Leukemia Cells
| العنوان: | Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates HOXA9 Gene Expression in t(4;11) Leukemia Cells |
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| المؤلفون: | Daniela Sarnataro, Fabio Cattaneo, Gabriella Esposito, Tiziana Fioretti, Mariateresa Zanobio, Maddalena Raia, Armando Cevenini, Rosario Ammendola |
| المساهمون: | Fioretti, T., Cevenini, A., Zanobio, M., Raia, M., Sarnataro, D., Cattaneo, F., Ammendola, R., Esposito, G. |
| المصدر: | International Journal of Molecular Sciences, Vol 22, Iss 4623, p 4623 (2021) |
| بيانات النشر: | MDPI AG, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | musculoskeletal diseases, MLL-AF4, Oncogene Proteins, Fusion, QH301-705.5, Chromosomal translocation, Target therapy, Catalysis, Translocation, Genetic, Inorganic Chemistry, Chimera (genetics), T(4, Cell Line, Tumor, hemic and lymphatic diseases, Gene expression, medicine, Nucleu, Physical and Theoretical Chemistry, Receptor, Fibroblast Growth Factor, Type 2, Biology (General), Molecular Biology, QD1-999, Spectroscopy, Gene knockdown, cell culture, AF4, integumentary system, Fibroblast growth factor receptor 2, Chemistry, Organic Chemistry, nucleus, Homeodomain Protein, General Medicine, HOXA9, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Computer Science Applications, Cell biology, Infant Acute Lymphoblastic Leukemia, Leukemia, Haematopoiesis, stomatognathic diseases, FGFR2, 11) leukemia, embryonic structures, Fibroblast Growth Factor 2, Myeloid-Lymphoid Leukemia Protein, Human |
| الوصف: | The chromosomal translocation t(4;11) marks an infant acute lymphoblastic leukemia associated with dismal prognosis. This rearrangement leads to the synthesis of the MLL-AF4 chimera, which exerts its oncogenic activity by upregulating transcription of genes involved in hematopoietic differentiation. Crucial for chimera’s aberrant activity is the recruitment of the AF4/ENL/P-TEFb protein complex. Interestingly, a molecular interactor of AF4 is fibroblast growth factor receptor 2 (FGFR2). We herein analyze the role of FGFR2 in the context of leukemia using t(4;11) leukemia cell lines. We revealed the interaction between MLL-AF4 and FGFR2 by immunoprecipitation, western blot, and immunofluorescence experiments; we also tested the effects of FGFR2 knockdown, FGFR2 inhibition, and FGFR2 stimulation on the expression of the main MLL-AF4 target genes, i.e., HOXA9 and MEIS1. Our results show that FGFR2 and MLL-AF4 interact in the nucleus of leukemia cells and that FGFR2 knockdown, which is associated with decreased expression of HOXA9 and MEIS1, impairs the binding of MLL-AF4 to the HOXA9 promoter. We also show that stimulation of leukemia cells with FGF2 increases nuclear level of FGFR2 in its phosphorylated form, as well as HOXA9 and MEIS1 expression. In contrast, preincubation with the ATP-mimetic inhibitor PD173074, before FGF2 stimulation, reduced FGFR2 nuclear amount and HOXA9 and MEIS1 transcript level, thereby indicating that MLL-AF4 aberrant activity depends on the nuclear availability of FGFR2. Overall, our study identifies FGFR2 as a new and promising therapeutic target in t(4;11) leukemia. |
| اللغة: | English |
| تدمد: | 1661-6596 1422-0067 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::565ff1d520271432133df191b391958cTest https://www.mdpi.com/1422-0067/22/9/4623Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....565ff1d520271432133df191b391958c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16616596 14220067 |
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