Meyer Stefan, Fergusson William D, Whetton Anthony D, Moreira-Leite Flavia, Pepper Stuart D, Miller Crispin, Saunders Emma K, White Daniel J, Will Andrew M, Eden Tim, Ikeda Hideyuki, Ullmann Reinhard, Tuerkmen Seval, Gerlach Antje, Klopocki Eva, Tönnies Holger
Academic Unit of Paediatric Oncology, Christie Hospital Trust, University of anchester, Manchester, UK.
Genes Chromosomes Cancer. 2007 Apr;46(4):359-72. doi: 10.1002/gcc.20417.
Fanconi anemia (FA) is an inherited disease with congenital abnormalities and an extreme risk of acute myeloid leukemia (AML). Genetic events occurring during malignant transformation in FA and the biology of FA-associated AML are poorly understood, but are often preceded by the development of chromosomal aberrations involving 3q26-29 in bone marrow of FA patients. We report here the molecular cytogenetic characterization of FA-derived AML cell lines SB1685CB and SB1690CB by conventional and array comparative genomic hybridization, fluorescence in situ hybridization, and SKY. We identified gains of a 3.7 MB chromosomal region on 3q26.2-26.31, which preceded transformation to overt leukemia. This region harbors the oncogenic transcription factor EVI1. A third FA-derived cell line, FA-AML1, carried a translocation with ectopic localization of 3q26 including EVI1. Rearrangements of 3q, which are rare in childhood AML, commonly result in overexpression of EVI1, which determines specific gene expression patterns and confers poor prognosis. We detected overexpression of EVI1 in all three FA-derived AML. Our results suggest a link between the FA defect, chromosomal aberrations involving 3q and overexpression of EVI1. We hypothesize that constitutional or acquired FA defects might be a common factor for the development of 3q abnormalities in AML. In addition, cryptic imbalances as detected here might account for overexpression of EVI1 in AML without overt 3q26 rearrangements.
范可尼贫血（FA）是一种伴有先天性异常且急性髓系白血病（AML）发病风险极高的遗传性疾病。FA恶性转化过程中发生的基因事件以及FA相关AML的生物学特性目前尚不清楚，但在FA患者骨髓中，通常先于涉及3q26 - 29的染色体畸变出现。我们在此报告通过常规及阵列比较基因组杂交、荧光原位杂交和光谱核型分析（SKY）对源自FA的AML细胞系SB1685CB和SB1690CB进行的分子细胞遗传学特征分析。我们鉴定出在3q26.2 - 26.31区域有一个3.7兆碱基的染色体区域获得，这发生在向明显白血病转化之前。该区域含有致癌转录因子EVI1。第三个源自FA的细胞系FA - AML1发生了易位，其中3q包括EVI1异位定位。3q重排在儿童AML中很少见，通常会导致EVI1过表达，这决定了特定的基因表达模式并预示预后不良。我们在所有三个源自FA的AML中均检测到EVI1过表达。我们的结果表明FA缺陷、涉及3q的染色体畸变与EVI1过表达之间存在联系。我们推测先天性或后天性FA缺陷可能是AML中3q异常发生的一个共同因素。此外，此处检测到的隐匿性失衡可能是导致无明显3q26重排的AML中EVI1过表达的原因。
