Schoch Claudia, Haferlach Torsten, Bursch Sabina, Gerstner Daniela, Schnittger Susanne, Dugas Martin, Kern Wolfgang, Löffler Helmut, Hiddemann Wolfgang
Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Genes Chromosomes Cancer. 2002 Sep;35(1):20-9. doi: 10.1002/gcc.10088.
Patients with acute myeloid leukemia (AML) and a complex aberrant karyotype have a poor outcome despite intensive antileukemic treatment. The aim of this study was to analyze in detail the genetic abnormalities in this subgroup of AML. Therefore, 125 AML cases with complex aberrant karyotype detected by G-banding were examined in addition with 24-color FISH and FISH with locus-specific probes for EGR1 (5q31), D7S522 (7q31), and TP53 (17p13), given that these regions are known to be commonly deleted in AML with a complex aberrant karyotype. The number of chromosome abnormalities per case varied from 3 to 30 (median 10). A gain of a whole chromosome was observed 131 times, with +8 (n = 30), +10 (n = 11), and +22 (n = 10) being the most frequent trisomies. A loss of a whole chromosome occurred 128 times. The chromosomes most often lost were 7 (n = 25), 18 (n = 24), and 17 (n = 17). Structural aberrations, leading to a gain or loss of chromosomal material, were detected 104 times and 433 times, respectively. Aberrations including only two chromosomes that seemed to be balanced were found only 19 times. Losses resulting from structural abnormalities most frequently involved 5q (n = 100), 17p (n = 47), and 12p (n = 29), whereas gains of 11q (n = 21), 21q (n = 19), and 8q (n = 11) were observed. Using locus-specific probes, deletions of the EGR1 locus (5q31), of 7q31, and the TP53 gene were observed in 103 (82%), 57 (46%), and 66 (53%) cases, respectively. In conclusion, in AML with a complex aberrant karyotype, loss of chromosomal material was observed much more often than gain. Unbalanced rearrangements leading to loss of chromosomal material are much more frequent than loss of whole chromosomes. These data suggest that in AML with a complex aberrant karyotype, loss of tumor-suppressor genes is a more important mechanism of leukemogenesis than activation of oncogenes, and that gene-dosage effects may play a significant role in the pathogenesis of this AML subtype.
尽管接受了强化抗白血病治疗，但急性髓系白血病（AML）且伴有复杂异常核型的患者预后较差。本研究的目的是详细分析该AML亚组中的基因异常情况。因此，对125例经G显带检测出复杂异常核型的AML病例，另外采用24色荧光原位杂交（FISH）以及针对EGR1（5q31）、D7S522（7q31）和TP53（17p13）的位点特异性探针进行FISH检测，因为已知在伴有复杂异常核型的AML中这些区域常发生缺失。每例患者的染色体异常数量从3条到30条不等（中位数为10条）。观察到整条染色体增加131次，其中+8（n = 30）、+10（n = 11）和+22（n = 10）是最常见的三体。整条染色体缺失发生128次。最常缺失的染色体是7号（n = 25）、18号（n = 24）和17号（n = 17）。分别检测到导致染色体物质增加或减少的结构畸变104次和433次。仅涉及两条看似平衡的染色体的畸变仅发现19次。结构异常导致的缺失最常累及5q（n = 100）、17p（n = 47）和12p（n = 29），而观察到11q（n = 21）、21q（n = 19）和8q（n = 11）增加。使用位点特异性探针，分别在103例（82%）、57例（46%）和66例（53%）病例中观察到EGR1位点（5q31）、7q31和TP53基因的缺失。总之，在伴有复杂异常核型的AML中，观察到染色体物质的缺失比增加更为常见。导致染色体物质缺失的不平衡重排比整条染色体缺失更为频繁。这些数据表明，在伴有复杂异常核型的AML中，肿瘤抑制基因的缺失是白血病发生比癌基因激活更重要的机制，并且基因剂量效应可能在这种AML亚型的发病机制中起重要作用。
