miR-15a/16-1 deletion in activated B cells promotes plasma cell and mature B-cell neoplasms
| العنوان: | miR-15a/16-1 deletion in activated B cells promotes plasma cell and mature B-cell neoplasms |
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| المؤلفون: | Irene M. Ghobrial, Vignesh Shanmugam, Juerg R. Straubhaar, Tomasz Sewastianik, Petr Jarolim, Mehmet Kemal Samur, Peter S. Dennis, Nikhil C. Munshi, Ruben D. Carrasco, Vinodh Pillai, Mary L. Bouxsein, David M. Dorfman, Jianjun Zhao, Jianli Wang, Helen Tanton, Jianhong Lin, Geraldine S. Pinkus, Daniel J. Brooks, Omar Nadeem, Ying Huang, Davide F. Robbiani, Bogdan Budnik, Meng Jiang, Keith Adler, Kenneth C. Anderson |
| المصدر: | Blood |
| بيانات النشر: | American Society of Hematology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Plasma Cells, Immunology, Chromosome Disorders, Plasma cell, Biology, Biochemistry, medicine, Animals, Humans, Neoplasms, Plasma Cell, Multiple myeloma, B-Lymphocytes, Lymphoid Neoplasia, Chromosomes, Human, Pair 13, Germinal center, Cancer, Chromosome, Cell Biology, Hematology, medicine.disease, Molecular biology, Lymphoma, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, MicroRNAs, medicine.anatomical_structure, Multigene Family, Lymphoma, Large B-Cell, Diffuse, Bone marrow, Hyperdiploidy, Chromosome Deletion, Multiple Myeloma, Gene Deletion, Plasmacytoma |
| الوصف: | Chromosome 13q deletion [del(13q)], harboring the miR-15a/16-1 cluster, is one of the most common genetic alterations in mature B-cell malignancies, which originate from germinal center (GC) and post-GC B cells. Moreover, miR-15a/16 expression is frequently reduced in lymphoma and multiple myeloma (MM) cells without del(13q), suggesting important tumor-suppressor activity. However, the role of miR-15a/16-1 in B-cell activation and initiation of mature B-cell neoplasms remains to be determined. We show that conditional deletion of the miR-15a/16-1 cluster in murine GC B cells induces moderate but widespread molecular and functional changes including an increased number of GC B cells, percentage of dark zone B cells, and maturation into plasma cells. With time, this leads to development of mature B-cell neoplasms resembling human extramedullary plasmacytoma (EP) as well as follicular and diffuse large B-cell lymphomas. The indolent nature and lack of bone marrow involvement of EP in our murine model resembles human primary EP rather than MM that has progressed to extramedullary disease. We corroborate human primary EP having low levels of miR-15a/16 expression, with del(13q) being the most common genetic loss. Additionally, we show that, although the mutational profile of human EP is similar to MM, there are some exceptions such as the low frequency of hyperdiploidy in EP, which could account for different disease presentation. Taken together, our studies highlight the significant role of the miR-15a/16-1 cluster in the regulation of the GC reaction and its fundamental context-dependent tumor-suppression function in plasma cell and B-cell malignancies. |
| تدمد: | 1528-0020 0006-4971 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a9af4e9d01b7dc0db27575d81e956889 https://doi.org/10.1182/blood.2020009088 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a9af4e9d01b7dc0db27575d81e956889 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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