DIFFERENT GENETIC PATHWAYS IN LEUKEMOGENESIS FOR PATIENTS PRESENTING WITH THERAPY-RELATED MYELODYSPLASIA AND THERAPY-RELATED ACUTE MYELOID-LEUKEMIA

Development of myelodysplasia (MDS) with subsequent progression to acu te myeloid leukemia (AML) is an example of the multistep process of ma lignant transformation in which each step often relates to genetic abn ormalities that can be directly seen as chromosomal aberrations. Thera py-related MDS and AML (t-MDS and t-AML) may serve as an ideal model f or a study of the genetic evolution of MDS and AML because chromosomal abnormalities are observed in most cases and because the disease is o ften 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 clin ical characteristics and the course of the disease. Balanced transloca tions to chromosome bands 11q23 and 21q22 represent primary steps in p athways leading directly to overt t-AML, Specific chromosomal deletion s 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 d eletion of its long arm (7q-) and deletion of the long arm of a chromo some 5 (5q-) were the most frequent primary abnormalities significantl y related to t-MDS, Loss of a whole chromosome 5 (-5) was also a prima ry 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 a bnormalities. 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 of chromosomes 5 and 7 were significantly associat ed with previous therapy with alkylating agents (P = .002), and balanc ed translocations to chromosome bands 3q26, 11q23, and 21q22 were sign ificantly associated with previous therapy with drugs targeting DNA-to poisomerase II (P < .00005). Other characteristic aberrations were not related to any specific type of therapy, The molecular changes believ ed to contribute to the development of t-MDS and t-AML have been ident ified for many of these chromosomal abnormalities. (C) 1995 by The Ame rican Society of Hematology.