MLL Munich Leukemia Laboratory, Munich, Germany.
Genes Chromosomes Cancer. 2012 Dec;51(12):1079-85. doi: 10.1002/gcc.21992. Epub 2012 Aug 8.
In acute myeloid leukemia (AML), increased ecotropic virus integration site 1 protein homolog (EVI1) gene expression is prognostically unfavorable. Subsets of cases show 3q26 rearrangements, such as inv(3)(q21q26)/t(3;3)(q21;q26), frequently accompanied by chromosome 7 abnormalities. We investigated whether cytogenetically cryptic EVI1 rearrangements may cause EVI1 overexpression in myeloid malignancies without 3q26 abnormalities and investigated 983 patients with AML (n = 606) or myelodysplastic syndromes (MDS; n = 377) with normal karyotype (CN-AML/CN-MDS, n = 594) or chromosome 7 abnormalities (n = 389) for EVI1 rearrangements using interphase FISH. We identified cytogenetically cryptic EVI1 rearrangements in 27 patients (19 AML, 8 MDS): inv(3)(p24q26) [n = 10]; t(3;21)(q26;q11) [n = 9]; and der(7)t(3;7)(q26;q21) [n = 8]. Elevated EVI1 expression was detected in nearly all cases with cryptic EVI1 rearrangements: Median %EVI1/ABL1 was 92.8 (range: 29.8-146.1) in inv(3)(p24q26), 104.9 (41.4-176.3) in t(3;21)(q26;q11), and 101.8 (4.4-210.4) in der(7)t(3;7)(q26;q21). This was similar to median %EVI1/ABL1 of 73.9 (range: 7.3-585.6) in an independent cohort of inv(3)(q21q26)/t(3;3)(q21;q26) and 67.1 (2.3-410.7) in other 3q26/EVI1 rearrangements. Healthy controls showed median EVI1 expression of 0.5 (range: 0.0-5.8). Using SNP microarray and sequencing analyses, the breakpoints of der(7)t(3;7)(q26;q21) were assigned to CDK6 and centromeric of EVI1, and of t(3;21)(q26;q11) to be within EVI1 and NRIP1. Median overall survival in patients with cryptic EVI1 rearrangements was short, comparable to patients with inv(3)(q21q26)/t(3;3)(q21;q26) or other EVI1 rearrangements. Cryptic EVI1 rearrangements contribute to explain the clinical heterogeneity of CN-AML and are associated with elevated EVI1 expression and an unfavorable prognosis. Screening for cryptic EVI1 rearrangements by FISH may be particularly appropriate in CN-AML with elevated EVI1 expression or in AML/MDS patients with chromosome 7 abnormalities.
在急性髓系白血病（AML）中，高表达的异位病毒整合位点 1 蛋白同源物（EVI1）基因预后不利。部分病例表现出 3q26 重排，如 inv(3)(q21q26)/t(3;3)(q21;q26)，常伴有染色体 7 异常。我们研究了细胞遗传学上隐匿的 EVI1 重排是否会导致无 3q26 异常的髓系恶性肿瘤中 EVI1 过表达，并使用间期 FISH 检测了 606 例 AML（n = 606）或骨髓增生异常综合征（MDS；n = 377）患者的 983 例核型正常（CN-AML/CN-MDS，n = 594）或染色体 7 异常（n = 389）患者中是否存在 EVI1 重排。我们鉴定了 27 例患者（19 例 AML，8 例 MDS）的隐匿性 EVI1 重排：inv(3)(p24q26)[n = 10]；t(3;21)(q26;q11)[n = 9]；和 der(7)t(3;7)(q26;q21)[n = 8]。几乎所有隐匿性 EVI1 重排患者的 EVI1 表达均升高：inv(3)(p24q26)中中位%EVI1/ABL1 为 92.8（范围：29.8-146.1），t(3;21)(q26;q11)中为 104.9（41.4-176.3），der(7)t(3;7)(q26;q21)中为 101.8（4.4-210.4）。这与独立队列中 inv(3)(q21q26)/t(3;3)(q21;q26)的中位%EVI1/ABL1（73.9，范围：7.3-585.6）和其他 3q26/EVI1 重排的中位%EVI1/ABL1（67.1，2.3-410.7）相似。健康对照者的 EVI1 表达中位数为 0.5（范围：0.0-5.8）。通过 SNP 微阵列和测序分析，der(7)t(3;7)(q26;q21)的断点被分配到 CDK6 和 EVI1 的着丝粒，t(3;21)(q26;q11)的断点在 EVI1 和 NRIP1 内。隐匿性 EVI1 重排患者的总生存期较短，与 inv(3)(q21q26)/t(3;3)(q21;q26)或其他 EVI1 重排患者相当。隐匿性 EVI1 重排有助于解释 CN-AML 的临床异质性，并与 EVI1 表达升高和预后不良相关。通过 FISH 筛查隐匿性 EVI1 重排可能特别适用于 EVI1 表达升高的 CN-AML 或伴有染色体 7 异常的 AML/MDS 患者。
