Mertens Daniel, Philippen Angela, Ruppel Melanie, Allegra Danilo, Bhattacharya Nupur, Tschuch Cordula, Wolf Stephan, Idler Irina, Zenz Thorsten, Stilgenbauer Stephan
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Leuk Lymphoma. 2009 Mar;50(3):502-5. doi: 10.1080/10428190902763509.
Loss of a critical region in 13q14.3 [del(13q)] is the most common genomic aberration in chronic lymphocytic leukemia (CLL), occurring in more than 50% of patients (Stilgenbauer et al., Oncogene 1998;16:1891 - 1897, Dohner et al., N Engl J Med 2000;343:1910 - 1916). Despite extensive investigations, no point mutations have been found in the remaining allele that would inactivate one of the candidate tumor suppressor genes and explain the pathomechanism postulated for this region. However, the genes in the region are significantly down-regulated in CLL cells, more than would be expected by gene dosage, and recently a complex epigenetic regulatory mechanism was identified for 13q14.3 in non-malignant cells that involves asynchronous replication timing and monoallelic expression of candidate tumor suppressor genes. Here, we propose a model of a multigenic pathomechanism in 13q14.3, where several tumor suppressor genes, including the miRNA genes miR-16-1 and miR-15a, are co-regulated by the two long non-coding RNA genes DLEU1 and DLEU2 that span the critical region. Furthermore, we propose these co-regulated genes to be involved in the same molecular pathways, thereby also forming a functional gene cluster. Elucidating the molecular and cellular function of the 13q14.3 candidate genes will shed light on the underlying pathomechanism of CLL.
13q14.3区域关键区域缺失[del(13q)]是慢性淋巴细胞白血病（CLL）中最常见的基因组畸变，超过50%的患者会出现这种情况（施蒂尔根鲍尔等人，《癌基因》1998年；16:1891 - 1897，多纳等人，《新英格兰医学杂志》2000年；343:1910 - 1916）。尽管进行了广泛研究，但在剩余等位基因中未发现会使候选肿瘤抑制基因之一失活并解释该区域假定发病机制的点突变。然而，该区域的基因在CLL细胞中显著下调，下调程度超过基因剂量所预期的水平，最近在非恶性细胞中为13q14.3鉴定出一种复杂的表观遗传调控机制，该机制涉及候选肿瘤抑制基因的异步复制时间和单等位基因表达。在此，我们提出13q14.3多基因发病机制模型，其中包括miRNA基因miR - 16 - 1和miR - 15a在内的多个肿瘤抑制基因由跨越关键区域的两个长链非编码RNA基因DLEU1和DLEU2共同调控。此外，我们提出这些共同调控的基因参与相同的分子途径，从而也形成一个功能基因簇。阐明13q14.3候选基因的分子和细胞功能将有助于揭示CLL的潜在发病机制。
