title: Replication errors in hematological neoplasias: genomic instability in progression of disease is different among different types of leukemia.
abstract: Genetic alteration, including genomic instability, is an ultimate step toward the malignant process. One approach to delineating replication errors in cancer cells is to determine the alterations of microsatellites, which are short, repeated nucleotide sequences existing throughout the genomes. We used a fluorescent system to assess microsatellite changes in seven loci (D2S123, D3S643, D5S107, LPL, D17S261, TP53, and D18S34) of 73 consecutive patients with various hematological neoplasias. De novo acute leukemia patients had a low frequency (<1%) of microsatellite alterations at each locus, and none of them demonstrated multiple microsatellite changes. In chronic myeloid leukemia patients, no microsatellite instability was detected in the chronic phase, whereas a relatively high frequency (25%) of multiple microsatellite changes was evident in the blastic phase, and half of these patients had multiple microsatellite changes. About 50% of the patients with myelodysplastic syndrome (MDS) and post-MDS acute myeloid leukemia (post-MDS AML) had microsatellite alterations. We next compared microsatellite alterations in two different hematological phases (MDS and post-MDS AML phases); 5 of 11 patients with post-MDS AML had de novo appearance of microsatellite instability during disease progression. This indicates that genomic instability at multiple microsatellite loci could occur either before or after leukemic transformation in MDS patients. We concluded that genomic instability in chronic myeloid leukemia might be linked to blastic transformation in combination with cytogenetic changes. In contrast, MDS patients had replication errors as a relatively early genetic event as well as a late genetic event. These results suggest that the involvement of genomic instability in the progression of disease is different among various types of leukemia.
authors.affiliation: First Department of Internal Medicine, Tokyo Medical College, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160, Japan.
authors.forename: J H
authors.initials: JH
authors.lastname: Ohyashiki
authors.forename: K
authors.initials: K
authors.lastname: Ohyashiki
authors.forename: S
authors.initials: S
authors.lastname: Aizawa
authors.forename: K
authors.initials: K
authors.lastname: Kawakubo
authors.forename: T
authors.initials: T
authors.lastname: Shimamoto
authors.forename: H
authors.initials: H
authors.lastname: Iwama
authors.forename: S
authors.initials: S
authors.lastname: Hayashi
authors.forename: K
authors.initials: K
authors.lastname: Toyama
mesh_terms: D004261:DNA Replication; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D018450:Disease Progression; D005453:Fluorescence; D019337:Hematologic Neoplasms / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods
chemical_list: D004273:DNA, Neoplasm