دورية أكاديمية
Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy.
| العنوان: | Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy. |
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| المؤلفون: | Oricchio, E., Ciriello, G., Jiang, M., Boice, M.H., Schatz, J.H., Heguy, A., Viale, A., de Stanchina, E., Teruya-Feldstein, J., Bouska, A., McKeithan, T., Sander, C., Tam, W., Seshan, V.E., Chan, W.C., Chaganti, R.S., Wendel, H.G. |
| المصدر: | The Journal of experimental medicine, vol. 211, no. 7, pp. 1379-1391 |
| سنة النشر: | 2014 |
| المجموعة: | Université de Lausanne (UNIL): Serval - Serveur académique lausannois |
| مصطلحات موضوعية: | Animals, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Cell Line, Tumor, Cyclin-Dependent Kinase 4/antagonists & inhibitors, Cyclin-Dependent Kinase 4/genetics, Cyclin-Dependent Kinase 4/metabolism, Cyclin-Dependent Kinase Inhibitor p15/genetics, Cyclin-Dependent Kinase Inhibitor p15/metabolism, Cyclin-Dependent Kinase Inhibitor p16/genetics, Cyclin-Dependent Kinase Inhibitor p16/metabolism, Humans, Lymphoma, Follicular/drug therapy, Follicular/genetics, Follicular/metabolism, Follicular/pathology, Male, Mice, Neoplasms, Experimental/drug therapy, Experimental/genetics, Experimental/metabolism, Experimental/pathology, Proto-Oncogene Proteins c-bcl-2/genetics, Proto-Oncogene Proteins c-bcl-2/metabolism, Retinoblastoma Protein/genetics, Retinoblastoma Protein/metabolism |
| الوصف: | Loss of cell cycle controls is a hallmark of cancer and has a well-established role in aggressive B cell malignancies. However, the role of such lesions in indolent follicular lymphoma (FL) is unclear and individual lesions have been observed with low frequency. By analyzing genomic data from two large cohorts of indolent FLs, we identify a pattern of mutually exclusive (P = 0.003) genomic lesions that impair the retinoblastoma (RB) pathway in nearly 50% of FLs. These alterations include homozygous and heterozygous deletions of the p16/CDKN2a/b (7%) and RB1 (12%) loci, and more frequent gains of chromosome 12 that include CDK4 (29%). These aberrations are associated with high-risk disease by the FL prognostic index (FLIPI), and studies in a murine FL model confirm their pathogenic role in indolent FL. Increased CDK4 kinase activity toward RB1 is readily measured in tumor samples and indicates an opportunity for CDK4 inhibition. We find that dual CDK4 and BCL2 inhibitor treatment is safe and effective against available models of FL. In summary, frequent RB pathway lesions in indolent, high-risk FLs indicate an untapped therapeutic opportunity. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0022-1007 |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/24913233; info:eu-repo/semantics/altIdentifier/eissn/1540-9538; info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_48D4D91B51197; https://serval.unil.ch/notice/serval:BIB_48D4D91B5119Test; urn:issn:0022-1007; https://serval.unil.ch/resource/serval:BIB_48D4D91B5119.P001/REF.pdfTest; http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_48D4D91B51197Test |
| DOI: | 10.1084/jem.20132120 |
| الإتاحة: | https://doi.org/10.1084/jem.20132120Test https://serval.unil.ch/notice/serval:BIB_48D4D91B5119Test https://serval.unil.ch/resource/serval:BIB_48D4D91B5119.P001/REF.pdfTest http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_48D4D91B51197Test |
| حقوق: | info:eu-repo/semantics/openAccess ; CC BY-NC-SA 4.0 ; https://creativecommons.org/licenses/by-nc-sa/4.0Test/ |
| رقم الانضمام: | edsbas.E6B6BA2D |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00221007 |
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| DOI: | 10.1084/jem.20132120 |