MMSET is the key molecular target in t(4;14) myeloma.
MMSET is the key molecular target in t(4;14) myeloma.
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DOI：
10.1038/bcj.2013.9
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发表时间：
2013-05-03
影响因子：
12.8
通讯作者：
Morgan, G. J.
中科院分区：
文献类型：
--
作者：
Mirabella, F.;Wu, P.;Wardell, C. P.;Kaiser, M. F.;Walker, B. A.;Johnson, D. C.;Morgan, G. J.
t (4; 14)（p16）。3;问。3)出现在15%的多发性骨髓瘤（MM）病例中，与其他生物学亚群相比，其预后明显较差。作为易位的结果，两个基因异常表达，成纤维细胞生长因子受体3 （FGFR3）和多发性骨髓瘤SET结构域蛋白MMSET (WHSC1/NSD2)，两者都具有潜在的致癌活性。1重要的是，FGFR3仅表现出微弱的转化活性，并在30%的患者中最终消失，2表明它不是主要的致癌因素。相反，MMSET基因过表达是普遍存在的，当它在实验中被敲除时，会抑制增殖、诱导细胞凋亡和改变细胞粘附，3-5表明它是该亚型MM的发病机制的核心。MMSET已知具有组蛋白甲基转移酶活性6，并且在发生骨髓瘤的早期被解除调控，因此可能是一个很好的治疗靶点。骨髓瘤患者的MMSET基因座具有复杂的基因组结构，在易位事件和RNA剪接后，产生了许多不同的转录本（图1）。最近发现的H/ACA盒RNA ACA11 （SCARNA22）增加了MMSET的遗传复杂性，该RNA在MMSET的内含子20中被发现，并且在t（4; 14）亚群中也过表达。这种小RNA已被认为是t (4; 14) MM发病机制的关键，提出了它可能构成主要治疗靶点的问题。盒状H/ACA RNA是一组从太古动物到哺乳动物保存下来的小核仁RNA （snoRNA）。这些rna通常与多蛋白复合物相关，通常作为rRNA和剪接体小核rna位点特异性假尿嘧啶化的指南。然而，它们也参与其他调控复合物，如端粒酶，但它们的全部生物学作用尚未完全阐明。超过90%的人类snoRNA基因编码在剪接的内含子内9，它们的表达与宿主基因的转录密切相关。9,10宿主基因转录后，内含子snorna通过核外溶活性被修剪成成熟的形式。mRNA剪接机制可能伴随snoRNA转录后成熟步骤，但在某些情况下，这些步骤是剪接独立的。11然而，在哺乳动物中有少数情况下，snoRNAs是独立转录的，例如，端粒酶RNA成分（terC）的基因或参与rrna前核溶解加工的RNA， 8,9，但这是罕见的事件。一系列实验表明，ACA11基因敲低会损害细胞增殖，使氧化应激反应失调，其过表达会下调核糖体蛋白基因的转录。7同一组的基础上,实验表明,t(4, 14)细胞系MMSET击倒,要么在转移等位基因(TKO)或nontranslocated等位基因(NTKO) ACA11较低水平相比看法。他们的父母的细胞系(KMS11)和一个正常的过表达MMSET,建议ACA11,而不是MMSET是关键致病基因t(4, 14)毫米。在以前的研究中,相同的TKO模型系统被用来证明的致癌效应
The t (4; 14)(p16. 3; q32. 3) is found in 15% of presenting multiple myeloma (MM) cases and is associated with a significantly worse prognosis than other biological subgroups. As a consequence of the translocation, two genes are aberrantly expressed, the fibroblast growth factor receptor 3 (FGFR3) and a multiple myeloma SET domain containing protein, MMSET (WHSC1/NSD2), both of which have potential oncogenic activity. 1 Importantly, FGFR3 shows only weak transforming activity and is eventually lost in 30% of patients, 2 suggesting that it is not the main oncogenic factor. In contrast, MMSET gene overexpression is universal, and when it is knocked down experimentally, there is inhibition of proliferation, induction of apoptosis and alteration of cell adhesion, 3–5 suggesting it is central to the pathogenesis of this subtype of MM. MMSET is known to have histone methyl transferase activity 6 and is deregulated early on in the genesis of developing myeloma, and could therefore constitute a good therapeutic target. The MMSET locus in t (4; 14) myeloma patients has a complicated genomic structure and after translocation events and RNA splicing, a number of different transcripts are generated (Figure 1). This genetic complexity of MMSET has been added to recently by the discovery of the H/ACA box RNA ACA11 (SCARNA22), that has been found within intron 20 of MMSET and is also overexpressed in the t (4; 14) subgroup. 7 This small RNA has been suggested to be key to the pathogenesis of t (4; 14) MM, raising the question that it may constitute the main therapeutic target.The box H/ACA RNAs are a group of small nucleolar RNA (snoRNA) conserved from Archea to mammals. These RNAs are generally associated with a multi-protein complex, and usually function as a guide to the site-specific pseudouridylation of rRNA and spliceosomal small nuclear RNAs. However, they are also involved in other regulatory complexes, such as telomerase, 8 but their full biological roles have not been completely elucidated. More than 90% of human snoRNA genes are encoded within spliced introns, 9 and their expression is closely linked to the transcription of the host gene. 9, 10 After host gene transcription, the intronic snoRNAs are trimmed to a mature form by exonucleolytic activities. The mRNA splicing machinery may chaperone snoRNA post-transcriptional maturation steps, but in some cases, these steps are splicing-independent. 11 However, there are a few cases in mammals where snoRNAs are independently transcribed, for instance, the gene for the telomerase RNA component (terC) or the RNAs involved in the pre-rRNA endonucleolytic processing, 8, 9 but this is a rare event. In a series of experiments it has been shown that ACA11 knockdown impairs cell proliferation and deregulates the oxidative stress response, and its overexpression downregulates the transcription of ribosomal protein genes. 7 The same group, on the basis of experiments showing that t (4; 14) cell lines knocked out for MMSET, either on the translocated allele (TKO) or on the nontranslocated allele (NTKO), have lower ACA11 levels compared wih their parental cell line (KMS11) with a normal overexpressed MMSET, suggested that ACA11, rather than MMSET, is the key pathogenic gene in t (4; 14) MM. In previous studies, the same TKO model system had been used to prove the oncogenic effect of
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