Telomere dynamics and genetic instability in disease progression of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by a Philadelphia (Ph) tran slocation creating a novel BCR-ABL oncoprotein, and CML patients have a chr onic phase for several years followed by an intractable blast cell prolifer ation, called blast transformation. In the blast phase, more than 60% of pa tients show additional cytogenetic changes, e. g., double Ph, +8, i(17q). I n this review, we would like to address genetic changes, including genome i nstability, cytogenetic changes, and telomere dynamics that relate to karyo typic 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 link ed to cell replication. Therefore, the Ph translocation might be a first ev ent to immortalize cell proliferation. In the blast phase, 50% of CML patie nts have high levels of elevated telomerase activity and the same number of patients had microsatellite changes. Of note is that most patients with te lomerase up-regulation in the blast phase had additional cytogenetic change s and >60% of them showed microsatellite changes at least at one locus. In contrast, most patients without telomerase activity did not show microsatel lite changes. These findings may indicate that telomerase up-regulation in the blast phase of CML patients is closely associated with microsatellite c hanges (representative of genome instability), while blast cells in the rem aining patients (30%) maintain their proliferative capability without micro satellite changes and telomerase up-regulation. This further suggests that there is also an unknown mechanism for genome stability without the process of telomerase upregulation in some patients with CML in blast crisis.