Migliazza A, Lombardi L, Rocchi M, Trecca D, Chang C C, Antonacci R, Fracchiolla N S, Ciana P, Maiolo A T, Neri A
Laboratorio di Ematologia Sperimentale e Genetica Molecolare, Istituto di Scienze Mediche, Università di Milano, Ospedale Maggiore IRCCS, Italy.
Blood. 1994 Dec 1;84(11):3850-60.
The NFKB2(lyt-10) gene codes for a protein that is a member of the NK-kappa B/rel family of transcription factors containing a DNA-binding rel domain and a carboxy-terminal ankyrin-like domain. The NFKB2 gene represents a candidate proto-oncogene, since it has been found to be involved in a chromosomal translocation t(10;14)(q24;q32) in one case of B-cell lymphoma and in gene rearrangements in various types of lymphoid malignancies. To elucidate the structural and functional consequences of NFKB2 rearrangements, we report the molecular characterization of three novel rearranged NFKB2 genes in lymphoid tumors. In one case of multiple myeloma (MM), cloning and sequencing analysis of reciprocal breakpoint sites showed that they occurred within intron 15 of the NFKB2 gene and led to the complete deletion of the 3' portion of the gene coding for the ankyrin domain. Fluorescent in situ hybridization (FISH) analysis showed that the novel regions involved in the NFKB2 rearrangement originated from chromosome 7q34, thus implying the occurrence of a t(7;10)(q34;q24) reciprocal chromosomal translocation. In one case of T-cell cutaneous lymphoma (CTCL) and in one of B-cell chronic lymphocytic leukemia (B-CLL), NFKB2 rearrangements occurred, respectively, within exons 18 and 20 of the gene and involved recombinations with distinct regions of chromosome 10q24. Molecular analysis suggested that these rearrangements may occur as a consequence of small internal chromosomal deletions. In both of these cases, the rearrangements led to specific carboxy-terminal truncations of NFKB2 generating abnormal transcripts that coded for proteins lacking portions of the ankyrin domain. These proteins localize in the nucleus, suggesting their constitutive activation in vivo. Overall, our results indicate that NFKB2 rearrangements in lymphoid neoplasia may occur by heterogeneous mechanisms, including internal chromosomal deletion or chromosomal translocation. The common consequence of these rearrangements appears to be the deletion of 3' sequences of NFKB2 leading to the production of carboxy-truncated constitutively nuclear proteins that may be involved in tumorigenesis.
NFKB2（lyt - 10）基因编码一种蛋白质，该蛋白质是转录因子NK - κB/rel家族的成员，包含一个DNA结合rel结构域和一个羧基末端锚蛋白样结构域。NFKB2基因代表一个候选原癌基因，因为在一例B细胞淋巴瘤中发现它参与了染色体易位t(10;14)(q24;q32)，并且在各种类型的淋巴恶性肿瘤中参与了基因重排。为了阐明NFKB2重排的结构和功能后果，我们报告了淋巴肿瘤中三个新的重排NFKB2基因的分子特征。在一例多发性骨髓瘤（MM）中，对相互断点位点的克隆和测序分析表明，它们发生在NFKB2基因的第15内含子内，并导致编码锚蛋白结构域的基因3'部分完全缺失。荧光原位杂交（FISH）分析表明，NFKB2重排涉及的新区域源自染色体7q34，因此意味着发生了t(7;10)(q34;q24)相互染色体易位。在一例T细胞皮肤淋巴瘤（CTCL）和一例B细胞慢性淋巴细胞白血病（B - CLL）中，NFKB2重排分别发生在该基因的第18外显子和第20外显子内，并涉及与染色体10q24不同区域的重组。分子分析表明，这些重排可能是小的内部染色体缺失的结果。在这两种情况下，重排都导致NFKB2特定的羧基末端截短，产生异常转录本，这些转录本编码缺少部分锚蛋白结构域的蛋白质。这些蛋白质定位于细胞核，表明它们在体内组成性激活。总体而言，我们的结果表明，淋巴肿瘤中的NFKB2重排可能通过异质机制发生，包括内部染色体缺失或染色体易位。这些重排的共同后果似乎是NFKB2的3'序列缺失，导致产生羧基截短且组成性定位于细胞核内的蛋白质，这些蛋白质可能参与肿瘤发生。
