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

ABSTRACT: The KLHL14 gene acquires frequent inactivating mutations in mature B cell malignancies, especially in the MYD88L265P, 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-?B activation. Consequently, KLHL14 inactivation allows MCD cells to maintain NF-?B signaling in the presence of ibrutinib. These findings reinforce the central role of My-T-BCR-dependent NF-?B signaling in MCD DLBCL and suggest that the genetic status of KLHL14 should be considered in clinical trials testing inhibitors of BTK and BCR signaling mediators in DLBCL.

SUBMITTER: Choi J

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

REPOSITORIES: biostudies-literature

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

Choi Jaewoo J Phelan James D JD Wright George W GW Häupl Björn B Huang Da Wei DW Shaffer Arthur L AL Young Ryan M RM Wang Zhuo Z Zhao Hong H Yu Xin X Oellerich Thomas T Staudt Louis M LM

Proceedings of the National Academy of Sciences of the United States of America 20200303 11

The <i>KLHL14</i> gene acquires frequent inactivating mutations in mature B cell malignancies, especially in the MYD88<sup>L265P</sup>, 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 th ...[more]

PMID: 32127472

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

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

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