Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia
| العنوان: | Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia |
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| المؤلفون: | Michael Haap, Lothar Kanz, Alexander R. Fuchs, Martin Müller, Hans-Georg Kopp, Stefan Wirths, David J. Müller, Yoshiteru Sasaki, Marc Sturm, Andreas Kirschniak, Melanie Märklin, Jonas S. Heitmann |
| المصدر: | Journal of Leukocyte Biology. 105:531-538 |
| بيانات النشر: | Oxford University Press (OUP), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Genetically modified mouse, Chronic lymphocytic leukemia, Immunology, B-cell receptor, Receptors, Antigen, B-Cell, Somatic hypermutation, Mice, Transgenic, Biology, Somatic evolution in cancer, Clonal Evolution, Gene Knockout Techniques, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Animals, Humans, Immunology and Allergy, B-cell lymphoma, NFATC Transcription Factors, breakpoint cluster region, Cell Biology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, V(D)J Recombination, Clone Cells, Mice, Inbred C57BL, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Cancer research, Immunoglobulin Heavy Chains |
| الوصف: | Chronic lymphocytic leukemia (CLL) can be defined as a clonal expansion of B cells with stereotypic BCRs. Somatic hypermutation of the BCR heavy chains (IGVH) defines a subgroup of patients with a better prognosis. In up to 10% of CLL cases, a transformation to an aggressive B cell lymphoma (Richter’s syndrome) with a dismal prognosis can be observed over time. NFAT proteins are transcription factors originally identified in T cells, which also play an important role in B cells. The TCL1 transgenic mouse is a well-accepted model of CLL. Upon B cell-specific deletion of NFAT2, TCL1 transgenic mice develop a disease resembling human Richter’s syndrome. Whereas TCL1 B cells exhibit tonic anergic BCR signaling characteristic of human CLL, loss of NFAT2 expression leads to readily activated BCRs indicating different BCR usage with altered downstream signaling. Here, we analyzed BCR usage in wild-type and TCL1 transgenic mice with and without NFAT2 deletion employing conventional molecular biology techniques and next-generation sequencing (NGS). We demonstrate that the loss of NFAT2 in CLL precipitates the selection of unmutated BCRs and the preferential usage of certain VDJ recombinations, which subsequently results in the accelerated development of oligoclonal disease. |
| تدمد: | 1938-3673 0741-5400 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::879f711e79cb919ea83a966962c76438Test https://doi.org/10.1002/jlb.2ab0218-076rrTest |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....879f711e79cb919ea83a966962c76438 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19383673 07415400 |
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