MYD 88 L265P mutations identify a prognostic gene expression signature and a pathway for targeted inhibition inCLL
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| المؤلفون: | Jennifer R. Brown, Divya Chaudhary, Bethany Tesar, Haesook T. Kim, Stacey M. Fernandes, Reuma Magori-Cohen, Lijian Yu, William F. Westlin, Siddha Kasar, Kevin Hoang, Ma. Reina Improgo, Wenyan Miao, Josephine L. Klitgaard |
| المصدر: | British Journal of Haematology. |
| بيانات النشر: | Wiley, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, Microarray, Genes, Immunoglobulin Heavy Chain, Biology, medicine.disease_cause, Cohort Studies, 03 medical and health sciences, Germline mutation, hemic and lymphatic diseases, Gene expression, medicine, Humans, Molecular Targeted Therapy, Gene, Aged, Mutation, Effector, Hematology, Middle Aged, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, Interleukin-1 Receptor-Associated Kinases, 030104 developmental biology, Myeloid Differentiation Factor 88, Cancer research, Cytokines, Female, Signal transduction, Transcriptome, IGHV@, Signal Transduction |
| الوصف: | The L265P somatic mutation in the Myeloid Differentiation Primary Response 88 (MYD88) gene is a recurrent mutation in chronic lymphocytic leukaemia (CLL). This mutation has functional effects in various haematological malignancies but its role in CLL remains to be fully elucidated. Here, we report that MYD88 L265P mutations are associated with mutated immunoglobulin heavy-chain gene (IGHV-M) status and that among IGHV-M patients, the presence of MYD88 L265P is associated with younger age at diagnosis. Using microarray and RNA-Seq gene expression analysis, we further observe that the MYD88 L265P mutation is associated with a distinctive gene expression signature that predicts both failure-free survival and overall survival. This association was validated in an independent cohort of patients. To determine whether MYD88 L265P mutations can be therapeutically exploited in CLL, we treated primary cells with an inhibitor of interleukin 1 receptor-associated kinase 4 (IRAK4), a critical effector of the MYD88 pathway. IRAK4 inhibition decreased downstream nuclear factor-κB signalling and cell viability in CLL cells, indicating the potential of the MYD88 pathway as a therapeutic target in CLL. |
| تدمد: | 1365-2141 0007-1048 |
| DOI: | 10.1111/bjh.15714 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5cd6220203b80bbed67ad8303952f94b https://doi.org/10.1111/bjh.15714 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5cd6220203b80bbed67ad8303952f94b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13652141 00071048 |
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| DOI: | 10.1111/bjh.15714 |