Kalla Claudia, Nentwich Hagen, Schlotter Magdalena, Mertens Daniel, Wildenberger Kathrin, Döhner Hartmut, Stilgenbauer Stephan, Lichter Peter
Abteilung Molekulare Genetik, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Genes Chromosomes Cancer. 2005 Feb;42(2):128-43. doi: 10.1002/gcc.20131.
Deletion of chromosome region 11q22-q23 defines a subgroup of patients with B-cell chronic lymphocytic leukemia (B-CLL) characterized by poor survival. Although the tumor-suppressor gene ATM in the consensus deletion region was found to be biallelically inactivated in about one third of B-CLL cases, in the majority of those who have this deletion, inactivation of the remaining ATM allele was not observed. To identify a second disease-associated gene, we investigated two B-CLL cases with translocation breakpoints in the critical 11q23 deletion region. In one case, a t(X;11)(q13;q23) was cloned and two novel genes were isolated. The breakpoint on 11q23 affected the ARHGAP20 gene, which encodes a protein predicted to be involved in the regulation of Rho family GTPases. The breakpoint on Xq13 occurred in BRWD3, which codes for a putative novel transcription factor. The rearrangement of ARHGAP20 and BRWD3 did not result in fusion transcripts, but it disrupted both genes. Mutation analysis of 28 B-CLL samples with monoallelic deletions and two B-CLL samples with 11q23 translocations detected no deleterious mutation in the remaining copy of ARHGAP20. Quantitative expression analysis in 22 B-CLLs revealed significant up-regulation of ARHGAP20 in CLL B cells, whereas BRWD3 was slightly down-regulated. Thus, deregulation of ARHGAP20 by altered gene expression or by gene disruption (but not point mutation) might be a general molecular mechanism of B-CLL leukemogenesis.
11号染色体区域11q22 - q23的缺失定义了一组生存预后较差的B细胞慢性淋巴细胞白血病（B - CLL）患者亚群。尽管在约三分之一的B - CLL病例中发现位于共有缺失区域的肿瘤抑制基因ATM发生双等位基因失活，但在大多数存在该缺失的患者中，未观察到剩余ATM等位基因的失活。为了鉴定第二个与疾病相关的基因，我们研究了两例在关键的11q23缺失区域存在易位断点的B - CLL病例。在其中一例中，克隆了t(X;11)(q13;q23)并分离出两个新基因。11q23上的断点影响了ARHGAP20基因，该基因编码一种预计参与Rho家族GTP酶调节的蛋白质。Xq13上的断点发生在BRWD3基因，该基因编码一种推定的新型转录因子。ARHGAP20和BRWD3的重排未产生融合转录本，但破坏了这两个基因。对28例单等位基因缺失的B - CLL样本和2例11q23易位的B - CLL样本进行突变分析，未在ARHGAP20的剩余拷贝中检测到有害突变。对22例B - CLL的定量表达分析显示，CLL B细胞中ARHGAP20显著上调，而BRWD3略有下调。因此，通过基因表达改变或基因破坏（而非点突变）导致的ARHGAP20失调可能是B - CLL白血病发生的一种普遍分子机制。
