Chromosome translocations in multiple myeloma
Chromosome translocations in multiple myeloma
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DOI：
10.1038/sj.onc.1204641
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发表时间：
2001-09-10
期刊：
影响因子：
8
通讯作者：
Kuehl, WM
中科院分区：
文献类型：
--
作者：
Bergsagel, PL;Kuehl, WM
多发性骨髓瘤（MM）是一种由体细胞突变、同种型转换的浆细胞（PC）引起的恶性肿瘤，通常起源于一种常见的良性PC肿瘤，称为意义不明的单克隆丙种球蛋白病（MGUS）。MM在骨髓内发展，然后发展到髓外阶段，从中产生MM细胞系。IgH易位的发生率随着疾病阶段的增加而增加：MGUS中为50%，髓内MM中为60-65%，髓外MM中为70-80%，MM细胞系中> 90%。初级，简单的相互IgH易位，这是目前在MGUS和MM，涉及许多合作伙伴，并提供了一个早期的永生化事件。四个染色体伴侣似乎占了大多数原发性IgH易位：11 q13（细胞周期蛋白D1）、6p 2l（细胞周期蛋白D3）、4p 16（FGFR 3和MMSET）和16 q23（c-maf）。它们主要由IgH开关重组中的错误介导，而较少由体细胞超突变中的错误介导，前者使内含子和3 '增强子解离，使得潜在的癌基因可以在每个衍生染色体上失调（例如，der 14上的FGFR 3和der 4上的MMSET）。有时不涉及IG基因座的继发性易位更复杂，并且不由B细胞特异性DNA修饰机制中的错误介导。它们涉及其他染色体伴侣，特别是8 q24（c-myc），并与肿瘤进展相关。与MM是长寿PC的恶性对应物一致，MM中原发性IgH易位失调的癌基因似乎不会产生抗凋亡作用，而是增加增殖和/或抑制分化。如此多不同的初级转化事件产生具有相同表型的肿瘤这一事实表明，转化细胞只有一种命运。
Multiple myeloma (MM), a malignant tumor of somatically mutated, isotype-switched plasma cells (PC), usually arises from a common benign PC tumor called Monoclonal Gammopathy of Undetermined Significance (MGUS). MM progresses within the bone marrow, and then to an extramedullary stage from which MM cell lines are generated. The incidence of IgH translocations increases with the stage of disease: 50% in MGUS, 60-65% in intramedullarly MM, 70-80% in extramedullary MM, and > 90% in MM cell lines. Primary, simple reciprocal IgH translocations, which are present in both MGUS and MM, involve many partners and provide an early immortalizing event. Four chromosomal partners appear to account for the majority of primary IgH translocations: 11q13 (cyclin D1), 6p2l (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf). They are mediated primarily by errors in IgH switch recombination and less often by errors in somatic hypermutation, with the former dissociating the intronic and 3 ' enhancer(s), so that potential oncogenes can be dysregulated on each derivative chromosome (e.g., FGFR3 on der14 and MMSET on der4). Secondary translocations, which sometimes do not involve Ig loci, are more complex, and are not mediated by errors in B cell specific DNA modification mechanisms. They involve other chromosomal partners, notably 8q24 (c-myc), and are associated with tumor progression. Consistent with MM being the malignant counterpart of a long-lived PC, oncogenes dysregulated by primary IgH translocations in MM do not appear to confer an anti-apoptotic effect, but instead increase proliferation and/or inhibit differentiation. The fact that so many different primary transforming events give rise to tumors with the same phenotype suggests that there is only a single fate available for the transformed cell.