Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma
Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma
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DOI：
10.1182/blood-2005-01-0034
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发表时间：
2005-07-01
期刊：
影响因子：
20.3
通讯作者：
Shaughnessy, J
中科院分区：
文献类型：
--
作者：
Bergsagel, PL;Kuehl, WM;Shaughnessy, J
对于多发性骨髓瘤（MM）和意义不明的癌前单克隆丙种球蛋白病（MGUS）肿瘤，假设有两种致癌途径：一种与高患病率的IgH易位相关的非超双螺旋体途径和一种与8条染色体的多发性三体相关的超双螺旋体途径。细胞周期蛋白D1，D2，或D3的表达似乎增加和/或失调，几乎所有的MM肿瘤，尽管他们的低增殖能力。易位可以直接失调CCND 1（11 q13）或CCND 3（6p 21），或MAF（16 q23）或MAFB（20 q11）靶向CCND 2的转录因子。CCND 1的双等位基因失调发生在近40%的肿瘤中，其中大多数是超二倍体。其他肿瘤表达增加的CCND 2，有或没有t（4;14）易位。使用基因表达谱鉴定5种复发性易位、特异性三体和细胞周期蛋白D基因表达，MM肿瘤可分为8个TC（易位/细胞周期蛋白D）组（11 q13、6p 21、4p 16、maf、D1、D1 + D2、D2和无），这些组似乎由早期致癌事件（可能是起始致癌事件）定义。然而，尽管随后发生进展事件，但这些组具有不同的基因表达谱，并且在骨病的患病率、复发频率和进展为髓外肿瘤方面也存在显著差异。
Two oncogenic pathways have been hypothesized for multiple myeloma (MM) and premalignant monoclonal gammopathy of undetermined significance (MGUS) tumors: a nonhyperdiplold pathway associated with a high prevalence of IgH-translocations and a hyperdiplold pathway associated with multiple trisomies of 8 chromosomes. Cyclin D1, D2, or D3 expression appears to be increased and/or dysregulated in virtually all MM tumors despite their low proliferative capacity. Translocations can directly dysregulate CCND1 (11q13) or CCND3 (6p21), or MAF (16q23) or MAFB (20q11) transcription factors that target CCND2. Biallelic dysregulation of CCND1 occurs in nearly 40 % of tumors, most of which are hyperdiploid. Other tumors express increased CCND2, either with or without a t(4;14) translocation. Using gene expression profiling to identify 5 recurrent translocations, specific trisomies, and expression of cyclin D genes, MM tumors can be divided into 8 TC (translocation/cyclin D) groups (11q13, 6p21, 4p16, maf, D1, D1 + D2, D2, and none) that appear to be defined by early, and perhaps initiating, oncogenic events. However, despite subsequent progression events, these groups have differing gene expression profiles and also significant differences in the prevalence of bone disease, frequency at relapse, and progression to extramedullary tumor.