Andersen M K, Christiansen D H, Kirchhoff M, Pedersen-Bjergaard J
Cytogenetic Laboratory, Department of Clinical Genetics, Section of Hematology/Oncology, The Juliane Marie Center, University Hospital, Copenhagen, Denmark.
Genes Chromosomes Cancer. 2001 May;31(1):33-41. doi: 10.1002/gcc.1115.
Gene amplification is a rare phenomenon in acute leukemia, but recently amplification of specific chromosome bands containing genes rearranged in leukemia-specific balanced chromosome translocations has been reported in a few cases. We detected duplication or amplification of chromosome band 11q23 with 3-7 copies of the MLL gene by fluorescence in situ hybridization in 12 out of 70 unselected patients with therapy-related myelodysplasia or acute myeloid leukemia (17%). In all but one case, the supernumerary copies of MLL were located to previously unidentified marker chromosomes or unbalanced translocations. In 4 of the 12 patients, 2-6 copies were located together on the same chromosome arm representing amplification, 7 patients had single, extra duplicated copies of MLL, whereas both amplification and duplication were observed in the same cell in 1 patient. Comparative genomic hybridization demonstrated gain of varying, often large parts of 11q in five patients. The MLL gene was shown to be unrearranged in all 12 patients. Seven out of eight patients with duplication or amplification of MLL had mutations of TP53. Patients with supernumerary copies of MLL were in general older (P = 0.007) and had a shorter survival (P < 0.001) compared to other patients. Duplication or amplification of MLL was significantly associated with a complex karyotype (P = 0.002), with deletion or loss of 5q (P = 0.001), and with prior therapy with alkylating agents. These results support the existence of a specific genetic pathway in t-MDS and t-AML with many previously unidentified chromosome aberrations demonstrated to represent extra copies of parts of 11q, including the unrearranged MLL gene.
基因扩增在急性白血病中是一种罕见现象，但最近有报道称，在少数病例中出现了特定染色体带的扩增，这些染色体带包含在白血病特异性平衡染色体易位中发生重排的基因。我们通过荧光原位杂交在70例未经选择的治疗相关骨髓增生异常综合征或急性髓系白血病患者中的12例（17%）中检测到11q23染色体带的重复或扩增，其中MLL基因有3 - 7个拷贝。除1例病例外，其余所有病例中MLL的额外拷贝均位于先前未识别的标记染色体或不平衡易位上。在12例患者中的4例中，2 - 6个拷贝共同位于同一染色体臂上，代表扩增；7例患者有单个额外的MLL重复拷贝，而在1例患者的同一个细胞中同时观察到扩增和重复。比较基因组杂交显示，5例患者的11q有不同程度的增加，通常是大片段增加。在所有12例患者中，MLL基因均未发生重排。8例MLL重复或扩增的患者中有7例存在TP53突变。与其他患者相比，MLL有额外拷贝的患者总体年龄较大（P = 0.007），生存期较短（P < 0.001）。MLL的重复或扩增与复杂核型（P = 0.002）、5q缺失或丢失（P = 0.001）以及先前接受烷化剂治疗显著相关。这些结果支持在治疗相关骨髓增生异常综合征和治疗相关急性髓系白血病中存在一种特定的遗传途径，其中许多先前未识别的染色体畸变被证明代表11q部分区域的额外拷贝，包括未重排的MLL基因。
