Regulation of B cell receptor-dependent NF-κB signaling by the tumor suppressor KLHL14.

ABSTRACT: The KLHL14 gene acquires frequent inactivating mutations in mature B cell malignancies, especially in the MYD88^L265P, CD79B mutant (MCD) genetic subtype of diffuse large B cell lymphoma (DLBCL), which relies on B cell receptor (BCR) signaling for survival. However, the pathogenic role of KLHL14 in DLBCL and its molecular function are largely unknown. Here, we report that KLHL14 is in close proximity to the BCR in the endoplasmic reticulum of MCD cell line models and promotes the turnover of immature glycoforms of BCR subunits, reducing total cellular BCR levels. Loss of KLHL14 confers relative resistance to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and promotes assembly of the MYD88-TLR9-BCR (My-T-BCR) supercomplex, which initiates prosurvival NF-κB activation.

SUBMITTER: Choi J 

PROVIDER: S-EPMC7084139 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature