杂乱突变激活多发性骨髓瘤中的非经典核因子κB通路。

Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.

作者信息

Keats Jonathan J, Fonseca Rafael, Chesi Marta, Schop Roelandt, Baker Angela, Chng Wee-Joo, Van Wier Scott, Tiedemann Rodger, Shi Chang-Xin, Sebag Michael, Braggio Esteban, Henry Travis, Zhu Yuan-Xiao, Fogle Homer, Price-Troska Tammy, Ahmann Gregory, Mancini Catherine, Brents Leslie A, Kumar Shaji, Greipp Philip, Dispenzieri Angela, Bryant Barb, Mulligan George, Bruhn Laurakay, Barrett Michael, Valdez Riccardo, Trent Jeff, Stewart A Keith, Carpten John, Bergsagel P Leif

机构信息

Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.

出版信息

Cancer Cell. 2007 Aug;12(2):131-44. doi: 10.1016/j.ccr.2007.07.003.

DOI:10.1016/j.ccr.2007.07.003

PMID:17692805

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2083698/

Abstract

Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma.

摘要

在许多肿瘤类型中都发现了NF-κB的激活，然而，这种激活与潜在基因突变的关联却很少见。对155份多发性骨髓瘤样本的高密度寡核苷酸阵列比较基因组杂交（CGH）和基因表达谱数据进行综合分析，发现一系列混杂的异常情况，约20%的患者中存在NF-κB失调。我们报告了十个基因的突变，这些突变导致TRAF2、TRAF3、CYLD、cIAP1/cIAP2失活，以及NFKB1、NFKB2、CD40、LTBR、TACI和NIK激活，主要导致非经典NF-κB途径的组成性激活，最常见的异常是TRAF3失活。这些结果突出了NF-κB途径在多发性骨髓瘤发病机制中的关键重要性。