IBTK contributes to B-cell lymphomagenesis in Eμ-myc transgenic mice conferring resistance to apoptosis
| العنوان: | IBTK contributes to B-cell lymphomagenesis in Eμ-myc transgenic mice conferring resistance to apoptosis |
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| المؤلفون: | Simona Ceglia, Giuseppe Fiume, Antonio Pisano, Enrico Iaccino, Giuseppe Scala, Ileana Quinto, Gaetanina Golino, Eleonora Vecchio, Giorgio Giurato, Selena Mimmi, Francesco Albano, Cristina Falcone, Domenico Britti |
| المصدر: | Cell Death & Disease Cell Death and Disease, Vol 10, Iss 4, Pp 1-14 (2019) |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Lymphoma, B-Cell, Cell Survival, Chronic lymphocytic leukemia, Immunology, Apoptosis, Bone Marrow Cells, Mice, Transgenic, Biology, medicine.disease_cause, Article, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, RNA interference, medicine, Animals, Humans, lcsh:QH573-671, B cell, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Knockout, B-Lymphocytes, Cell Biology, lcsh:Cytology, Cell Cycle Checkpoints, Cell cycle, medicine.disease, Mice, Inbred C57BL, Haematopoiesis, HEK293 Cells, 030104 developmental biology, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Tumor Suppressor Protein p53, Carcinogenesis, Spleen, HeLa Cells |
| الوصف: | Increasing evidence supports the involvement of IBTK in cell survival and tumor growth. Previously, we have shown that IBTK RNA interference affects the wide genome expression and RNA splicing in cell-type specific manner. Further, the expression of IBTK gene progressively increases from indolent to aggressive stage of chronic lymphocytic leukemia and decreases in disease remission after therapy. However, the role of IBTK in tumorigenesis has not been elucidated. Here, we report that loss of the murine Ibtk gene raises survival and delays tumor onset in Eμ-myc transgenic mice, a preclinical model of Myc-driven lymphoma. In particular, we found that the number of pre-cancerous B cells of bone marrow and spleen is reduced in Ibtk−/−Eμ-myc mice owing to impaired viability and increased apoptosis, as measured by Annexin V binding, Caspase 3/7 cleavage assays and cell cycle profile analysis. Instead, the proliferation rate of pre-cancerous B cells is unaffected by the loss of Ibtk. We observed a direct correlation between Ibtk and myc expression and demonstrated a Myc-dependent regulation of Ibtk expression in murine B cells, human hematopoietic and nonhematopoietic cell lines by analysis of ChIP-seq data. By tet-repressible Myc system, we confirmed a Myc-dependent expression of IBTK in human B cells. Further, we showed that Ibtk loss affected the main apoptotic pathways dependent on Myc overexpression in pre-cancerous Eμ-myc mice, in particular, MCL-1 and p53. Of note, we found that loss of IBTK impaired cell cycle and increased apoptosis also in a human epithelial cell line, HeLa cells, in Myc-independent manner. Taken together, these results suggest that Ibtk sustains the oncogenic activity of Myc by inhibiting apoptosis of murine pre-cancerous B cells, as a cell-specific mechanism. Our findings could be relevant for the development of IBTK inhibitors sensitizing tumor cells to apoptosis. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c58cb3c86b7bcd1465eedcee0b107002 http://hdl.handle.net/11386/4723158 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c58cb3c86b7bcd1465eedcee0b107002 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |