Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
Haematologica. 2010 Jan;95(1):153-7. doi: 10.3324/haematol.2009.010157. Epub 2009 Jul 31.
Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) shows constitutive NF-kappaB activity in the malignant lymphocyte-predominant (LP) cells. Constitutive NF-kappaB activity also plays a central pathogenetic role in classical Hodgkin's lymphoma (cHL), where inactivating mutations in the NFKBIA and TNFAIP3 genes, coding for the negative NF-kappaB regulators IkappaBalpha and A20, respectively, contribute to NF-kappaB activation. To determine whether mutations in NFKBIA and TNFAIP3 are also involved in the pathogenesis of NLPHL these genes were sequenced from microdissected LP cells of 10 primary NLPHL. We also studied DEV, the only cell line proposedly derived from LP cells, after we had confirmed its derivation from NLPHL by gene expression analysis. A heterozygous somatic missense mutation in the NFKBIA gene was found in one NLPHL, and a heterozygous, possibly subclonal, two base pair insertion in TNFAIP3 in another case. The low mutation frequency and the absence of biallelic destructive mutations propose a minor contribution of NFKBIA and TNFAIP3 mutations to the NF-kappaB activity of NLPHL, suggesting different mechanisms of NF-kappaB activation in NLPHL and cHL.
结节性淋巴细胞为主型霍奇金淋巴瘤 (NLPHL) 在恶性淋巴细胞为主型 (LP) 细胞中表现出固有 NF-κB 活性。固有 NF-κB 活性也在经典霍奇金淋巴瘤 (cHL) 中发挥着核心发病作用，在 cHL 中，编码负性 NF-κB 调节剂 IkappaBalpha 和 A20 的 NFKBIA 和 TNFAIP3 基因的失活突变分别导致 NF-κB 的激活。为了确定 NFKBIA 和 TNFAIP3 的突变是否也参与 NLPHL 的发病机制，我们对 10 例原发性 NLPHL 的 LP 细胞进行了微切割，并对其进行了测序。在通过基因表达分析确认其源自 NLPHL 后，我们还研究了 DEV，这是唯一一条据称源自 LP 细胞的细胞系。在一个 NLPHL 中发现了 NFKBIA 基因的杂合性体细胞错义突变，而在另一个 NLPHL 中发现了 TNFAIP3 的杂合性、可能是亚克隆的两个碱基对插入。低突变频率和无双等位基因破坏性突变表明 NFKBIA 和 TNFAIP3 突变对 NLPHL 的 NF-κB 活性的贡献较小，提示 NLPHL 和 cHL 中 NF-κB 激活的不同机制。
