Telomere dynamics and genetic instability in disease progression of chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is characterized by a Philadelphia (Ph) translocation creating a novel BCR-ABL oncoprotein, and CML patients have a chronic phase for several years followed by an intractable blast cell proliferation, called blast transformation. In the blast phase, more than 60% of patients show additional cytogenetic changes, e. g., double Ph, +8, i(17q). In this review, we would like to address genetic changes, including genome instability, cytogenetic changes, and telomere dynamics that relate to karyotypic instability. In the chronic phase, approximately 60% of CML patients show reduced telomere length without highly elevated telomerase activity or microsatellite alterations, indicating that telomere reduction may be linked to cell replication. Therefore, the Ph translocation might be a first event to immortalize cell proliferation. In the blast phase, 50% of CML patients have high levels of elevated telomerase activity and the same number of patients had microsatellite changes. Of note is that most patients with telomerase up-regulation in the blast phase had additional cytogenetic changes and >60% of them showed microsatellite changes at least at one locus. In contrast, most patients without telomerase activity did not show microsatellite changes. These findings may indicate that telomerase up-regulation in the blast phase of CML patients is closely associated with microsatellite changes (representative of genome instability), while blast cells in the remaining patients (30%) maintain their proliferative capability without microsatellite changes and telomerase up-regulation. This further suggests that there is also an unknown mechanism for genome stability without the process of telomerase up-regulation in some patients with CML in blast crisis.
Ohyashiki
K
K
First Department of Internal Medicine, Tokyo Medical University, Japan. ohyashik@rr.iij4u.or.jp
Iwama
H
H
Tauchi
T
T
Shimamoto
T
T
Hayashi
S
S
Ando
K
K
Kawakubo
K
K
Ohyashiki
J H
JH
D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D010677:Philadelphia Chromosome; D016615:Telomere / Q000378:metabolism*; D014178:Translocation, Genetic