Regulation of B cell receptor-dependent NF-κB signaling by the tumor suppressor KLHL14
Regulation of B cell receptor-dependent NF-κB signaling by the tumor suppressor KLHL14
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DOI：
10.1073/pnas.1921187117
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发表时间：
2020-03-17
影响因子：
11.1
通讯作者：
Staudt, Louis M.
中科院分区：
文献类型：
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作者：
Choi, Jaewoo;Phelan, James D.;Staudt, Louis M.
KLHL14基因在成熟B细胞恶性肿瘤中获得频繁的失活突变，特别是在弥漫性大B细胞淋巴瘤（DLBCL）的MYD88(L265P)， CD79B突变（MCD）遗传亚型中，其依赖于B细胞受体（BCR）信号传导存活。然而，KLHL14在DLBCL中的致病作用及其分子功能在很大程度上是未知的。在这里，我们报道了KLHL14在MCD细胞系模型的内质网中与BCR非常接近，并促进BCR亚基的未成熟糖型的转换，降低细胞总BCR水平。KLHL14的缺失赋予了对布鲁顿酪氨酸激酶（BTK）抑制剂伊鲁替尼的相对抗性，并促进MYD88-TLR9-BCR （My-T-BCR）超复合物的组装，从而启动促生存NF-kappa B激活。因此，KLHL14失活允许MCD细胞在伊鲁替尼存在下维持NF-kappa B信号传导。这些发现强化了my - t -BCR依赖性NF-kappa B信号在MCD DLBCL中的核心作用，并提示在DLBCL中检测BTK和BCR信号介质抑制剂的临床试验中应考虑KLHL14的遗传状况。
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-kappa B activation. Consequently, KLHL14 inactivation allows MCD cells to maintain NF-kappa B signaling in the presence of ibrutinib. These findings reinforce the central role of My-T-BCR-dependent NF-kappa 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.