Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia
| العنوان: | Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia |
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| المؤلفون: | Timothy G. Amos, Janith A. Seneviratne, Quentin Van Thillo, Hannah McCalmont, Wai L. Tam, Jan Cools, Ira W. Deveson, Jolien De Bie, Sofie Demeyer, Nancy Boeckx, Richard B. Lock, Vicki Zhai, Sarah Provost, Kiyotaka Isobe, Junko Takita, Anne Uyttebroeck, Heidi Segers, Olga Gielen, Daniel R. Carter, Ethan P. Oxley, Charles E. de Bock, Bram Sweron, Maximilian M. Garwood, Belamy B. Cheung, Glenn M. Marshall, Ross A. Dickins, Anushree Balachandran, Itaru Kato, Ellen Geerdens, Sofia Omari |
| المصدر: | Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021) Nature Communications |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Oncogene Proteins, Fusion, Carcinogenesis, T-Lymphocytes, General Physics and Astronomy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease_cause, Proto-Oncogene Mas, GTP Phosphohydrolases, Fusion gene, Mice, 0302 clinical medicine, hemic and lymphatic diseases, T Cell Transcription Factor 1, Cancer genetics, beta Catenin, Bone Marrow Transplantation, Mutation, Gene knockdown, Multidisciplinary, Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Science, T cell, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Proto-Oncogene Proteins, medicine, Animals, Humans, Acute lymphocytic leukaemia, SPI1, Membrane Proteins, Oncogenes, General Chemistry, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, HEK293 Cells, 030104 developmental biology, Catenin, Trans-Activators, Cancer research, Transcriptome |
| الوصف: | Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction. SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin. |
| وصف الملف: | Electronic; application/pdf |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4729d788d0d4d91953687b3a369bc0d1 https://doi.org/10.1038/s41467-021-24442-9 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4729d788d0d4d91953687b3a369bc0d1 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 20411723 |
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