Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation
المؤلف | Alinari, Lapo |
المؤلف | Mahasenan, Kiran V. |
المؤلف | Yan, Fengting |
المؤلف | Karkhanis, Vrajesh |
المؤلف | Chung, Ji-Hyun |
المؤلف | Smith, Emily M. |
المؤلف | Quinion, Carl |
المؤلف | Smith, Porsha L. |
المؤلف | Kim, Lisa |
المؤلف | Patton, John T. |
المؤلف | Lapalombella, Rosa |
المؤلف | Yu, Bo |
المؤلف | Wu, Yun |
المؤلف | Roy, Satavisha |
المؤلف | De Leo, Alessandra |
المؤلف | Pileri, Stefano |
المؤلف | Agostinelli, Claudio |
المؤلف | Ayers, Leona |
المؤلف | Bradner, James E. |
المؤلف | Chen-Kiang, Selina |
المؤلف | Elemento, Olivier |
المؤلف | Motiwala, Tasneem |
المؤلف | Majumder, Sarmila |
المؤلف | Byrd, John C. |
المؤلف | Jacob, Samson |
المؤلف | Sif, Said |
المؤلف | Li, Chenglong |
المؤلف | Baiocchi, Robert A. |
تاريخ الإتاحة | 2016-11-20T08:53:23Z |
تاريخ النشر | 2015-04-16 |
اسم المنشور | Blood |
المعرّف | http://dx.doi.org/10.1182/blood-2014-12-619783 |
الاقتباس | Alinari L, Mahasenan KV, Yan F, et al. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood. 2015;125(16):2530-2543. |
الرقم المعياري الدولي للكتاب | 0006-4971 |
الملخص | Epigenetic events that are essential drivers of lymphocyte transformation remain incompletely characterized. We used models of Epstein-Barr virus (EBV)–induced B-cell transformation to document the relevance of protein arginine methyltransferase 5 (PRMT5) to regulation of epigenetic-repressive marks during lymphomagenesis. EBV+ lymphomas and transformed cell lines exhibited abundant expression of PRMT5, a type II PRMT enzyme that promotes transcriptional silencing of target genes by methylating arginine residues on histone tails. PRMT5 expression was limited to EBV-transformed cells, not resting or activated B lymphocytes, validating it as an ideal therapeutic target. We developed a first-in-class, small-molecule PRMT5 inhibitor that blocked EBV-driven B-lymphocyte transformation and survival while leaving normal B cells unaffected. Inhibition of PRMT5 led to lost recruitment of a PRMT5/p65/HDAC3-repressive complex on the miR96 promoter, restored miR96 expression, and PRMT5 downregulation. RNA-sequencing and chromatin immunoprecipitation experiments identified several tumor suppressor genes, including the protein tyrosine phosphatase gene PTPROt, which became silenced during EBV-driven B-cell transformation. Enhanced PTPROt expression following PRMT5 inhibition led to dephosphorylation of kinases that regulate B-cell receptor signaling. We conclude that PRMT5 is critical to EBV-driven B-cell transformation and maintenance of the malignant phenotype, and that PRMT5 inhibition shows promise as a novel therapeutic approach for B-cell lymphomas. |
راعي المشروع | This work was supported by grants from the American Society of Hematology/European Hematology Association (L.Alinari), the Leukemia & Lymphoma Society Translational Research Project (LLS TRP) (R.A.B.), Friends of Jason Gould Foundation (R.A.B., P.L.S., J.T.P.), The Ohio State University Drug Development Institute (R.A.B., C.L.), National Institutes of Health, National Institute of Neurological Disorders and Stroke grant R21NS071346 (R.A.B., C.L.) and National Cancer Institute grant R01CA116093 (S.S., R.A.B.). |
اللغة | en |
الناشر | American Society of Hematology |
الموضوع | Cancer etiology Lymphoma Tumor Suppressor Proteins/genetics |
النوع | Article |
الصفحات | 2530-2543 |
رقم العدد | 16 |
رقم المجلد | 125 |
ESSN | 1528-0020 |
الملفات في هذه التسجيلة
الملفات | الحجم | الصيغة | العرض |
---|---|---|---|
لا توجد ملفات لها صلة بهذه التسجيلة. |
هذه التسجيلة تظهر في المجموعات التالية
-
العلوم البيولوجية والبيئية [881 items ]