Trisomies in Hematologic Malignancies

Abstract: Acquired clonal chromosome aberrations, closely associated with leukemogenesis, are found in many hematologic malignancies. Although the balanced rearrangements, such as translocations and inversions, are the ones most commonly thought of in the context of leukemias, gains of chromosomes ? e.g.., trisomies ? are also frequent. Little is known about the biologic outcome, the pathogenetic significance, or the mechanism behind the formation of the latter genetic changes. The aim of the present thesis was to address these issues, focusing on trisomy 8 as the sole cytogenetic change in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and on high hyperdiploidy ? gains of multiple chromosomes ? in childhood acute lymphoblastic leukemia (ALL). In the first two articles, AML and MDS cases with +8 as the seemingly sole abnormality were studied with fluorescence in situ hybridization (FISH) analysis and high-resolution genome-wide array-based comparative genome hybridization (array CGH), respectively, in order to determine whether this chromosome abnormality was truly isolated or if there were additional, cytogenetically cryptic, anomalies present. Whereas multicolor-FISH, FISH with partial chromosome paint and subtelomeric probes for 8p and 8q, and FISH with probes specific for four leukemia-associated chromosome 8 genes failed to reveal any hidden genetic changes, array CGH identified twelve previously undetected imbalances, involving 0.2 ? 4.9 Mb and many genes, of putative importance in the leukemogenesis. Thus, it was shown that trisomy 8 is not always the primary genetic event, even when it is the sole anomaly seen with standard cytogenetic methods. In articles III and IV, the formation of hyperdiploidy and the possibility of imprinting effects related to the parental origin of the chromosomes gained in this cytogenetic subgroup were investigated. Combining the results from the two studies, it could, for the first time, be demonstrated that hyperdiploidy most frequently arises by a simultaneous gain of chromosomes in a single abnormal cell division, with a subset of cases occurring by other pathways. Furthermore, preferential duplication of maternal or paternal homologues was not seen for any of the commonly gained chromosomes in these investigations. Hence, imprinting effects resulting from such skewness could be excluded as the pathogenetically important outcome of the extra chromosomes in hyperdiploid childhood ALL. In summary, the results presented in this thesis have extended our knowledge of trisomies in malignant hematologic disorders and increased the understanding of their significance in the leukemogenic processes.