Stevens Servi J C, Meers Laurence E C, Albrechts Jozefa C M, Mebis-Verhees Karien, Bos Gerard M J, Engelen John J M, Janssen Jannie W H
Department of Clinical Genetics, Unit of Cytogenetics, Maastricht University Medical Center, Maastricht, the Netherlands.
Cancer Genet Cytogenet. 2010 Aug;201(1):48-51. doi: 10.1016/j.cancergencyto.2010.05.002.
A 55-year-old man sought care for aggressive acute lymphoblastic leukemia (ALL), which developed 8 years after he had received chemotherapeutic treatment for nephrotic syndrome. The sole cytogenetic abnormality observed in bone marrow-derived metaphases was a t(4;11)(q21;q23), which is a frequently occurring translocation in ALL. However, subsequent reverse transcriptase-polymerase chain reaction for the expected mixed lineage leukemia [trithorax homolog, Drosophila] (MLL)-AFF1 fusion transcript was negative. Further fluorescence in situ hybridization (FISH) analysis narrowed the 4q21 breakpoint down to a 250-kb region proximal of AFF1. This comprised four genes, of which septin11 (SEPT11) was further analyzed. Reverse transcriptase-polymerase chain reaction revealed expression of a chimeric MLL-SEPT11 transcript, thus identifying what is to our knowledge a hitherto undescribed translocation in ALL. Sequence analysis of cDNA showed in-frame fusion of MLL exon 11 to SEPT11 exon 2. This MLL-SEPT11 fusion is cytogenetically indistinguishable from the recurrent t(4;11)(q21;q23). Thus, it is crucial to characterize cytogenetic aberrations in leukemia by molecular methods, even in cases where a known recurrent translocation is presumed. This report expands the spectrum of ALL-related translocations and hypothesizes on the mechanism leading to the MLL-SEPT11 fusion. Five septins have been identified thus far as MLL fusion partners in leukemia. Their putative oncogenic role may be related to forced MLL dimerization by the septin coiled coil and GTP-binding domains, which could convert MLL to an oncogene.
一名55岁男性因侵袭性急性淋巴细胞白血病（ALL）前来就医，该病在他接受肾病综合征化疗8年后发生。在骨髓来源的中期相中观察到的唯一细胞遗传学异常是t(4;11)(q21;q23)，这是ALL中常见的易位。然而，随后针对预期的混合谱系白血病[果蝇同源的三体同源物]（MLL）-AFF1融合转录本的逆转录酶-聚合酶链反应为阴性。进一步的荧光原位杂交（FISH）分析将4q21断点缩小到AFF1近端的一个250 kb区域。该区域包含四个基因，其中对septin11（SEPT11）进行了进一步分析。逆转录酶-聚合酶链反应显示了嵌合的MLL-SEPT11转录本的表达，从而确定了据我们所知ALL中一种迄今未描述的易位。cDNA的序列分析显示MLL外显子11与SEPT11外显子2的读框内融合。这种MLL-SEPT11融合在细胞遗传学上与常见的t(4;11)(q21;q23)无法区分。因此，即使在假定存在已知的常见易位的情况下，通过分子方法对白血病中的细胞遗传学异常进行表征也至关重要。本报告扩展了ALL相关易位的范围，并对导致MLL-SEPT11融合的机制进行了推测。迄今为止，已确定五种septin蛋白为白血病中MLL的融合伴侣。它们假定的致癌作用可能与septin卷曲螺旋和GTP结合域导致的MLL强制二聚化有关，这可能将MLL转化为癌基因。
