Pedersen-Bjergaard J, Pedersen M, Roulston D, Philip P
Department of Hematology L 4132, Finsen Center, Rigshospitalet, University Hospital of Copenhagen, Denmark.
Blood. 1995 Nov 1;86(9):3542-52.
Development of myelodysplasia (MDS) with subsequent progression to acute myeloid leukemia (AML) is an example of the multistep process of malignant transformation in which each step often relates to genetic abnormalities that can be directly seen as chromosomal aberrations. Therapy-related MDS and AML (t-MDS and t-AML) may serve as an ideal model for a study of the genetic evolution of MDS and AML because chromosomal abnormalities are observed in most cases and because the disease is often diagnosed early due to a close patient follow-up. The cytogenetic characteristics at diagnosis were studied in 137 consecutive cases of t-MDS and t-AML, including 22 new cases, and correlated with the clinical characteristics and the course of the disease. Balanced translocations to chromosome bands 11q23 and 21q22 represent primary steps in pathways leading directly to overt t-AML. Specific chromosomal deletions or losses, on the other hand, represent primary or secondary events in alternative pathways leading to t-MDS with potential for subsequent transformation to overt t-AML. Loss of a whole chromosome 7 (-7) or deletion of its long arm (7q-) and deletion of the long arm of a chromosome 5 (5q-) were the most frequent primary abnormalities significantly related to t-MDS. Loss of a whole chromosome 5 (-5) was also a primary event, but surprisingly, was observed equally in t-MDS and in t-AML. Deletion of chromosome 13, including bands q13q14, was another less common primary aberration of t-MDS. Except for -7 and del(13q), these primary aberrations were most often observed together with secondary abnormalities. These included balanced aberrations involving band 3q26 and various deletions of chromosome 3, a gain of a whole chromosome 8, deletions of the short arm or loss of chromosomes 12 and 17, loss of a whole chromosome 18, and deletions of the short arm of chromosome 21. Deletions or loss or chromosomes 5 and 7 were significantly associated with previous therapy with alkylating agents (P = .002), and balanced translocations to chromosome bands 3q26, 11q23, and 21q22 were significantly associated with previous therapy with drugs targeting DNA-topoisomerase II (P < .00005). Other characteristic aberrations were not related to any specific type of therapy. The molecular changes believed to contribute to the development of t-MDS and t-AML have been identified for many of these chromosomal abnormalities.
骨髓增生异常综合征（MDS）发展为后续的急性髓系白血病（AML）是恶性转化多步骤过程的一个例子，其中每个步骤通常与可直接视为染色体畸变的基因异常相关。治疗相关的MDS和AML（t-MDS和t-AML）可能是研究MDS和AML基因演变的理想模型，因为在大多数病例中可观察到染色体异常，且由于对患者密切随访，该疾病常能早期诊断。对137例连续的t-MDS和t-AML病例（包括22例新病例）的诊断时细胞遗传学特征进行了研究，并将其与临床特征及疾病进程相关联。向染色体带11q23和21q22的平衡易位是直接导致明显t-AML的途径中的主要步骤。另一方面，特定的染色体缺失或丢失代表了导致t-MDS并有可能随后转化为明显t-AML的替代途径中的主要或次要事件。整条染色体7缺失（-7）或其长臂缺失（7q-）以及染色体5长臂缺失（5q-）是与t-MDS显著相关的最常见主要异常。整条染色体5缺失（-5）也是一个主要事件，但令人惊讶的是，在t-MDS和t-AML中均有同等程度的观察到。包括带q13q14的染色体13缺失是t-MDS另一种较不常见的主要畸变。除了-7和del(13q)外，这些主要畸变最常与次要异常一起出现。这些次要异常包括涉及带3q26的平衡畸变和染色体3的各种缺失、整条染色体8的增加、染色体12和17短臂的缺失或整条染色体18的缺失以及染色体21短臂的缺失。染色体5和7的缺失或丢失与先前使用烷化剂治疗显著相关（P = 0.002），向染色体带3q26、11q23和21q22的平衡易位与先前使用靶向DNA拓扑异构酶II的药物治疗显著相关（P < 0.00005）。其他特征性畸变与任何特定类型的治疗均无关。对于许多这些染色体异常，已确定了被认为促成t-MDS和t-AML发生的分子变化。
