A critical role for the NFkB pathway in multiple myeloma.
A critical role for the NFkB pathway in multiple myeloma.
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DOI：
10.18632/oncotarget.109
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发表时间：
2010-05
期刊：
影响因子：
--
通讯作者：
Kuehl WM
中科院分区：
文献类型：
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作者：
Demchenko YN;Kuehl WM
NFkB转录因子在多种b细胞肿瘤（包括多发性骨髓瘤（MM））的存活和增殖中发挥关键作用。研究表明，NFkB在MM肿瘤中的激活主要是由APRIL和BAFF配体的外部信号传导引起的，这些配体刺激正常浆细胞上的受体以及恶性前单克隆γ病（MGUS）和MM肿瘤上的受体。然而，在MM进展过程中发生的突变以及构成性激活NFkB的突变有望降低肿瘤细胞对骨髓微环境的依赖性。这些突变可以选择性地激活经典或替代的NFkB途径，但通常在MM中这两种途径都被激活。值得注意的是，激活任何一种NFkB途径都会导致MM细胞系的类似反应。这种替代途径的频繁激活将MM与其他b细胞肿瘤区分开来，后者更频繁地具有突变，预计仅激活经典的NFkB途径。考虑到MGUS和MM肿瘤对NFkB通路激活的强烈依赖性，靶向外源信号和两种NFkB通路的联合抑制似乎是MM肿瘤的一种有吸引力的治疗方法。
NFkB transcription factors play a key role in the survival and proliferation of many kinds of B-cell tumors, including multiple myeloma (MM). It was shown that NFkB activation in MM tumors results mainly from extrinsic signaling by APRIL and BAFF ligands that stimulate receptors on normal plasma cells as well as on pre-malignant monoclonal gammopathy of undetermined significance (MGUS) and MM tumors. However, the mutations that occur during MM progression and that constitutively activate NFkB would be expected to decrease dependence of tumor cells on the bone marrow microenvironment. These mutations can activate the classical or alternative NFkB pathways selectively, but usually both pathways are activated in MM. Significantly, activation of either NFkB pathway leads to a similar response of MM cell lines. This frequent activation of the alternative pathway distinguishes MM from other B-cell tumors, which more frequently have mutations that are predicted to activate only the classical NFkB pathway. Given the strong dependence of MGUS and MM tumors on NFkB pathway activation, inhibition by a combination of targeting extrinsic signaling plus both NFkB pathways appears to be an attractive therapeutic approach in MM tumors.