期刊
NATURE
卷 546, 期 7657, 页码 302-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature22353
关键词
-
资金
- Italian Association for Cancer Research
- Giovanni Armenise/Harvard Foundation
- National Institutes of Health
- European Research Council through FIRB IDEAS
- European Research Council [268921]
- ICGC MMML-Seq grant [01KU1002]
- ICGC-DE-Mining grant [01KU1505G]
- e:BIO MMML-MYC-SYS grant [036166]
- KinderKrebsInitiative Buchholz/Holm-Seppensen
- U. Veronesi Foundation
- Fondazione Beretta
- European Research Council (ERC) [268921] Funding Source: European Research Council (ERC)
Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival(1-3), surface BCR expression is conserved in most mature B-cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival(4-7). Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies(8,9). Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3 beta) activity to support MYC-controlled gene expression. BCR- tumour cells exhibit increased GSK3 beta activity and are rescued from their competitive growth disadvantage by GSK3 beta inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3 beta activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR- tumour cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据