MYD88 L265P mutations identify a prognostic gene expression signature and a pathway for targeted inhibition in CLL.
Br J Haematol
; 184(6): 925-936, 2019 03.
Article
em En
| MEDLINE
| ID: mdl-30537114
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Leucemia Linfocítica Crônica de Células B
/
Fator 88 de Diferenciação Mieloide
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos