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Normalization of previously shortened telomere length under treatment with imatinib argues against a preexisting telomere length deficit in normal hematopoietic stem cells from patients with chronic myeloid leukemia

Normalization of previously shortened telomere length under treatment with imatinib argues against a preexisting telomere length deficit in normal hematopoietic stem cells from patients with chronic myeloid leukemia
Normalization of previously shortened telomere length under treatment with imatinib argues against a preexisting telomere length deficit in normal hematopoietic stem cells from patients with chronic myeloid leukemia
Telomeres are composed of TTAGGG repeats and associated proteins. In somatic cells, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence. In previous studies, we described substantial and disease stage-specific telomere shortening in peripheral blood (PB) leukocytes from patients with chronic myeloid leukemia (CML). Here, we sought to determine whether age-adjusted telomere length in PB granulocytes (deltaTEL(gran)) is associated with response to treatment with the selective tyrosine kinase inhibitor imatinib. A total of 517 samples from 206 patients in chronic phase (CP), accelerated phase (AP), and blast crisis (BC) before and up to 706 days after initiation of imatinib therapy (median: 144 days) were analyzed by quantitative fluorescence in situ hybridization of interphase cells in suspension (Flow-FISH); telomere fluorescence was expressed in molecular equivalents of soluble fluorochrome units (MESF). Telomere length in samples from start of treatment up to day 144 was significantly shorter (mean +/- SE; -1.5 +/- 0.3 kMESF) compared to samples from patients treated for more than 144 days (-0.8 +/- 0.3 kMESF, p = 0.035). In patients with repeated measurements, a significant increase in telomere length under treatment was observed. Median telomere length in major remission was found to be significantly longer compared to patients without response to treatment measured either by cytogenetics (n = 246, p < 0.05), interphase FISH (n = 204, p = 0.002), or quantitative RT-PCR (n = 371, p < 0.05). In conclusion, the increase in telomere length under treatment with imatinib reflects a shift from Ph+ to Ph- cells in the PB of patients with CML.
hematopoietic stem cells, stem cells, fluorescence, telomere, therapy, adolescent, interphase, leukemia, blood, aging, metabolism, pathology, leukocytes, humans, middle aged, cytogenetics, aged, stem-cells, piperazines, proteins, pharmacology, myeloid, non-u.s.gov't, cytology, patients, tyrosine, drug effects, pyrimidines, 80 and over, in situ hybridization, male, female, blast crisis, research support, adult, granulocytes, protein, chronic, telomerase, cell division, disease, germany
0077-8923
26-38
Brummendorf, T.H.
794e2962-27b6-4bff-a83e-064df4ef98c5
Ersoz, I.
ee9c1391-5782-4397-b1e7-8d3714132c59
Hartmann, U.
9f97b424-619f-440f-813a-333a0570fd35
Balabanov, S.
56e829c4-5bfd-4af0-9b60-1926919ac77f
Wolke, H.
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Paschka, P.
3a97b303-face-4de6-8a34-e3c6bd98c0f9
Lahaye, T.
97333448-5919-4fa2-b1d7-d4bcc51733f3
Berner, B.
27ea7941-87a7-4c0b-be18-2956d939ff5e
Bartolovic, K.
350f3b6e-d207-463b-8e3a-f12074cc7d9b
Kreil, S.
2404ac13-cdaa-43a3-913b-adceb79e598f
Berger, U.
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Gschaidmeier, H.
46d97d80-f9c6-4286-af8a-407d4a282058
Bokemeyer, C.
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Hehlmann, R.
753d719b-7bf8-4f74-bfdc-6d5d47e5d2c7
Dietz, K.
2f4811b9-91b5-486e-b005-0261cff0e4cf
Lansdorp, P.M.
867cc5a6-723f-4f73-b7d0-cb97aff8b369
Kanz, L.
bf95abce-9bc1-4356-b254-7ad4c060d1ca
Hochhaus, A.
4c0b9da4-adfa-4253-8af7-78cec9e9a24f
Brummendorf, T.H.
794e2962-27b6-4bff-a83e-064df4ef98c5
Ersoz, I.
ee9c1391-5782-4397-b1e7-8d3714132c59
Hartmann, U.
9f97b424-619f-440f-813a-333a0570fd35
Balabanov, S.
56e829c4-5bfd-4af0-9b60-1926919ac77f
Wolke, H.
42909582-d4d7-411a-ae13-07b9fdc22f4f
Paschka, P.
3a97b303-face-4de6-8a34-e3c6bd98c0f9
Lahaye, T.
97333448-5919-4fa2-b1d7-d4bcc51733f3
Berner, B.
27ea7941-87a7-4c0b-be18-2956d939ff5e
Bartolovic, K.
350f3b6e-d207-463b-8e3a-f12074cc7d9b
Kreil, S.
2404ac13-cdaa-43a3-913b-adceb79e598f
Berger, U.
440811e1-e1c2-4f54-a435-b6dd61853857
Gschaidmeier, H.
46d97d80-f9c6-4286-af8a-407d4a282058
Bokemeyer, C.
11f174a9-1b7c-452a-985c-744cd170722b
Hehlmann, R.
753d719b-7bf8-4f74-bfdc-6d5d47e5d2c7
Dietz, K.
2f4811b9-91b5-486e-b005-0261cff0e4cf
Lansdorp, P.M.
867cc5a6-723f-4f73-b7d0-cb97aff8b369
Kanz, L.
bf95abce-9bc1-4356-b254-7ad4c060d1ca
Hochhaus, A.
4c0b9da4-adfa-4253-8af7-78cec9e9a24f

Brummendorf, T.H., Ersoz, I., Hartmann, U., Balabanov, S., Wolke, H., Paschka, P., Lahaye, T., Berner, B., Bartolovic, K., Kreil, S., Berger, U., Gschaidmeier, H., Bokemeyer, C., Hehlmann, R., Dietz, K., Lansdorp, P.M., Kanz, L. and Hochhaus, A. (2003) Normalization of previously shortened telomere length under treatment with imatinib argues against a preexisting telomere length deficit in normal hematopoietic stem cells from patients with chronic myeloid leukemia. Annals of the New York Academy of Sciences, 996 (Hematopoietic S), 26-38. (doi:10.1111/j.1749-6632.2003.tb03229.x).

Record type: Article

Abstract

Telomeres are composed of TTAGGG repeats and associated proteins. In somatic cells, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence. In previous studies, we described substantial and disease stage-specific telomere shortening in peripheral blood (PB) leukocytes from patients with chronic myeloid leukemia (CML). Here, we sought to determine whether age-adjusted telomere length in PB granulocytes (deltaTEL(gran)) is associated with response to treatment with the selective tyrosine kinase inhibitor imatinib. A total of 517 samples from 206 patients in chronic phase (CP), accelerated phase (AP), and blast crisis (BC) before and up to 706 days after initiation of imatinib therapy (median: 144 days) were analyzed by quantitative fluorescence in situ hybridization of interphase cells in suspension (Flow-FISH); telomere fluorescence was expressed in molecular equivalents of soluble fluorochrome units (MESF). Telomere length in samples from start of treatment up to day 144 was significantly shorter (mean +/- SE; -1.5 +/- 0.3 kMESF) compared to samples from patients treated for more than 144 days (-0.8 +/- 0.3 kMESF, p = 0.035). In patients with repeated measurements, a significant increase in telomere length under treatment was observed. Median telomere length in major remission was found to be significantly longer compared to patients without response to treatment measured either by cytogenetics (n = 246, p < 0.05), interphase FISH (n = 204, p = 0.002), or quantitative RT-PCR (n = 371, p < 0.05). In conclusion, the increase in telomere length under treatment with imatinib reflects a shift from Ph+ to Ph- cells in the PB of patients with CML.

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Published date: 24 January 2003
Keywords: hematopoietic stem cells, stem cells, fluorescence, telomere, therapy, adolescent, interphase, leukemia, blood, aging, metabolism, pathology, leukocytes, humans, middle aged, cytogenetics, aged, stem-cells, piperazines, proteins, pharmacology, myeloid, non-u.s.gov't, cytology, patients, tyrosine, drug effects, pyrimidines, 80 and over, in situ hybridization, male, female, blast crisis, research support, adult, granulocytes, protein, chronic, telomerase, cell division, disease, germany

Identifiers

Local EPrints ID: 59531
URI: http://eprints.soton.ac.uk/id/eprint/59531
ISSN: 0077-8923
PURE UUID: d99cd8a4-234a-4923-81cb-b78e48ba221d

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Date deposited: 03 Sep 2008
Last modified: 08 Jan 2022 16:04

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Contributors

Author: T.H. Brummendorf
Author: I. Ersoz
Author: U. Hartmann
Author: S. Balabanov
Author: H. Wolke
Author: P. Paschka
Author: T. Lahaye
Author: B. Berner
Author: K. Bartolovic
Author: S. Kreil
Author: U. Berger
Author: H. Gschaidmeier
Author: C. Bokemeyer
Author: R. Hehlmann
Author: K. Dietz
Author: P.M. Lansdorp
Author: L. Kanz
Author: A. Hochhaus

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