MYD 88 L265P mutations identify a prognostic gene expression signature and a pathway for targeted inhibition inCLL
| Autor: | 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 |
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| Rok vydání: | 2018 |
| Předmět: |
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 |
| Zdroj: | British Journal of Haematology. |
| ISSN: | 1365-2141 0007-1048 |
| DOI: | 10.1111/bjh.15714 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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