title: Telomere shortening correlates with prognostic score at diagnosis and proceeds rapidly during progression of chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) is associated increased stem cell turnover. We have previously shown that short telomeres in chronic phase (CP) predict for early progression to blast phase (BP). Poor prognostic score patients may therefore exhibit increased telomere loss at diagnosis and/or a greater than normal rate of loss during the disease course. We prospectively studied newly diagnosed CML patients for degree of telomere loss; measured telomere length in CML patients at all stages of disease; and performed follow-up sampling according to cytogenetic response to imatinib mesylate. Using flow-FISH, telomere length in peripheral blood leucocytes (PBL) from 32 consecutive newly diagnosed patients was measured (with ex-vivo expanded T-cells as an internal BCR-ABL negative control), in addition to 65 samples from all CML stages and 7 paired CP/BP samples. Fifty-five normal individuals served as a control population. Patients who attained either a complete cytogenetic response (CCR, 0% Ph+, n = 10) or no CR (100% Ph+, n = 11) underwent follow-up measurement. All statistical tests were two sided. Telomeres in accelerated phase (AP) and BP patients were significantly shorter than in CP, and mean telomere shortening was significantly greater in high-risk score than low-risk patients (P < 0.05) at diagnosis. The rate of shortening during disease progression was 10-20 times the rate observed in normal granulocytes. BP samples had undergone at least 30-60 additional divisions from baseline Ph- telomere length. Our findings show that telomere shortening in CML is greatest in high-risk score patients at diagnosis, and occurs rapidly during disease progression.
authors.affiliation: HOS, Division of Cancer Sciences and Molecular Pathology, Glasgow Royal Infirmary University of Glasgow, Glasgow G31 2ER, UK. mwd3z@clinmed.gla.ac.uk
authors.forename: Mark
authors.initials: M
authors.lastname: Drummond
authors.forename: Anne
authors.initials: A
authors.lastname: Lennard
authors.forename: Tim
authors.initials: T
authors.lastname: Brûmmendorf
authors.forename: Tessa
authors.initials: T
authors.lastname: Holyoake
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D002478:Cells, Cultured; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010879:Piperazines / Q000627:therapeutic use; D011379:Prognosis; D011743:Pyrimidines / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016615:Telomere / Q000378:metabolism*; D013997:Time Factors
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate