Classical and/or alternative NF-κB pathway activation in multiple myeloma
Classical and/or alternative NF-κB pathway activation in multiple myeloma
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DOI：
10.1182/blood-2009-09-243535
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发表时间：
2010-04-29
期刊：
影响因子：
20.3
通讯作者：
Kuehl, W. Michael
中科院分区：
文献类型：
--
作者：
Demchenko, Yulia N.;Glebov, Oleg K.;Kuehl, W. Michael
涉及核因子- κ B （nf - κ B）途径的突变存在于至少17%的多发性骨髓瘤（MM）肿瘤和40%的MM细胞系（MMCLs）中。这些突变是明显的进展事件，使MM肿瘤不再依赖于激活NF-kappa b的骨髓信号。对51个MMCLs的研究揭示了这些突变的作用机制，以及NF-kappa b的经典激活与替代激活的重要性。首先，只有一个突变（NFKB2）选择性地激活替代途径，而几个突变(CYLD, NFKB1，和TACI)选择性地激活经典通路。然而，大多数影响NF-kappa b诱导激酶（NIK）水平的突变（NIK、TRAF2、TRAF3、cIAP1&2和CD40）激活了另一种途径，但通常是两种途径。其次，我们确认了TRAF2在调节NIK降解中的关键作用，而TRAF3增强了ciap1 /2介导的MM中NIK的蛋白酶体降解，但不是必需的。第三，通过转染选择性激活经典或替代NF-kappa B途径，我们发现在一个MMCL中基因表达几乎相同的变化，而在另一个MMCL中变化相似，但不相同。我们的研究结果表明，通过激活nf - κ B通路的突变，MM肿瘤可以从骨髓微环境中获得更多的自主性。[血液杂志];2010;115(17):3541-3552 .]
Mutations involving the nuclear factor-kappa B (NF-kappa B) pathway are present in at least 17% of multiple myeloma (MM) tumors and 40% of MM cell lines (MMCLs). These mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NF-kappa B. Studies on a panel of 51 MMCLs provide some clarification of the mechanisms through which these mutations act and the significance of classical versus alternative activation of NF-kappa B. First, only one mutation (NFKB2) selectively activates the alternative pathway, whereas several mutations (CYLD, NFKB1, and TACI) selectively activate the classical pathway. However, most mutations affecting NF-kappa B-inducing kinase (NIK) levels (NIK, TRAF2, TRAF3, cIAP1&2, and CD40) activate the alternative but often both pathways. Second, we confirm the critical role of TRAF2 in regulating NIK degradation, whereas TRAF3 enhances but is not essential for cIAP1/2-mediated proteasomal degradation of NIK in MM. Third, using transfection to selectively activate the classical or alternative NF-kappa B pathways, we show virtually identical changes in gene expression in one MMCL, whereas the changes are similar albeit nonidentical in a second MMCL. Our results suggest that MM tumors can achieve increased autonomy from the bone marrow microenvironment by mutations that activate either NF-kappa B pathway. (Blood. 2010; 115(17): 3541-3552)