Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry

Chronic myeloid leukemia (CML) is a clonal, multilineage myeloproliferative disorder characterized by the Philadelphia chromosome (Ph) and a marked ex pansion of myeloid cells. Previous studies have indicated that the telomere length in blood cells may indicate their replicative history. However, the large variation in telomere length between individuals complicates the use of this parameter in CML and other hematologic disorders. To circumvent th is problem, we compared the telomere length in peripheral blood or bone mar row cells with purified normal (Ph-) T lymphocytes from the same CML patien t using fluorescence in situ hybridization and flow cytometry. Overall telo mere fluorescence was significantly reduced in Ph+ cells from patients with CML compared to blood leukocytes from normal individuals (P < 0.001) or no rmal (Ph-) T lymphocytes from the same individuals (n = 51, P < 0.001), Cel ls from patients in accelerated phase or blast phase (AP/BP) showed signifi cantly shorter average telomere length than cells from patients in chronic phase (CP, P = 0.02) or cytogenetic remission (CR, P = 0.03), Patients in C P who subsequently developed BP within 2 years had significantly shorter te lomeres than those who did not develop BP for at least 2 years(P < 0.05). A ccelerated replication-dependent telomere shortening in Ph+ versus Ph- leuk ocytes supports previous evidence that Ph+ stem cells cycle more actively t han their counterparts in normal individuals. Our data further suggest that telomere shortening may serve as a surrogate marker of disease progression in patients with CP CML, supporting a mechanistic link between CML stem ce ll turnover, genetic instability, and malignant evolution in this disease. (C) 2000 by The American Society of Hematology.