Blood, 1 January 2003, Vol. 101, No. 1, pp. 375-375
CORRESPONDENCE
To the editor:
Telomere length in peripheral blood granulocytes
reflects response to treatment with imatinib in patients with chronic
myeloid leukemia
Telomeres are composed of TTAGGG repeats and
associated proteins.1 In somatic cells, telomere repeats
are lost with each cell division, eventually leading to genetic
instability and cellular senescence.2 In previous studies,
we and others described substantial and disease stage-specific
telomere shortening in Philadelphia chromosome-positive
(Ph+) peripheral blood (PB) leukocytes from patients with
chronic myeloid leukemia (CML).3,4
The selective tyrosine kinase inhibitor imatinib blocks
phosphorylation of tyrosine residues by occupying the adenosine
triphosphate (ATP) site of BCR-ABL.5 Clinical
phase 2 studies in CML revealed that the drug is capable of inducing
major cytogenetic remissions in 60% of chronic phase (CP) patients
previously treated with interferon 
6, and even
in about 26% of patients in accelerated phase (AP)7 and in
15% in myeloid blast crisis (BC).8
In the current study, we sought to determine whether age-adjusted
telomere length in PB granulocytes (
TELgran) is
correlated with response to treatment with imatinib.
A total of 517 samples from 206 patients in CP, AP, and BC before and
up to 706 days after initiation of imatinib therapy (median, 144 days)
were analyzed by fluorescence in situ hybridization and flow cytometry
(flow-FISH), telomere fluorescence was expressed in
molecular equivalents of soluble fluorochrome units
(MESF).9 Age-adjusted telomere length decreased
dependent on disease stage from samples derived from patients
in CP (median, 
1.1 kMESF; 25-75 percentile; 3.3 to
1.2 kMESF), AP (1.6 kMESF; 3.9 to 1.3 kMESF), and BC
(1.8 kMESF; 3.7 to 0.5 kMESF). However, the degree of
telomere shortening was substantially less than what we had observed in
previous studies performed in the "pre-imatinib era" of CML
treatment.3 Therefore, we investigated the correlation between the duration of imatinib treatment and telomere length in the
PB. Telomere length in samples from start of treatment up to day 144 was significantly shorter (mean ± SE; 1.5 ± 0.3 kMESF)
compared with samples from patients treated for more than 144 days
(0.8 ± 0.3 kMESF, P = .035).
In order to analyze whether the increase in telomere length
observed during imatinib treatment was due to a shift from
Ph+ to Ph
cells in the PB of these patients,
samples were grouped based on the degree of remission achieved either
in the bone marrow (BM) measured by conventional cytogenetics
(Figure 1A)
or in the PB by quantitative reverse transcriptase-polymerase chain
reaction (RT-PCR) (Figure 1B). Telomere length in samples from
patients in major or complete cytogenetic remission (median,
0.3 kMESF; 25-75 percentile; 2.8 to 2.6 kMESF; n = 58)
was found to be longer compared with samples from patients with minor
(1.4 kMESF; 3.4 to 1.2 kMESF; n = 44) or without
cytogenetic response (1.7 kMESF; 3.9 to 0.6 kMESF; n = 144, P < .05 for difference between major and no cytogenetic response; Figure 1A). When the samples were grouped
according to molecular remission10 (Figure 1B),
median telomere length in samples from patients in good molecular
response condition (BCR-ABL/ABL ratio < 2%,
0.6 kMESF; 2.3 to 3.0 kMESF; n = 44) was not different from
age-adjusted controls but differed significantly from samples obtained
from patients with no molecular response (BCR-ABL/ABL
ratio > 14%, 1.8 kMESF; 4.1 to 0.3 kMESF; n = 278,
P < .05). Patients with intermediate molecular response (BCR-ABL/ABL ratio 2%-14%) showed an intermediate degree of
telomere reduction (0.9 kMESF; 3.2 to 2.1 kMESF;
n = 49).
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| Figure 1.
Age-adjusted telomere length in patients with CML.
(A) Cytogenetic remission in the BM and (B) molecular response in the
PB by quantitative RT-PCR.
|
|
In summary, our observations reflect a steadily increasing
fraction of Ph cells (with normal or only slightly
reduced telomere length) contributing to the peripheral blood cell pool
in patients receiving imatinib treatment. Cytogenetic and
molecular responses achieved during imatinib therapy are
associated with a normalization of previously shortened telomere length
arguing against a preexisting telomere length deficit in normal
hematopoietic stem cells from patients with CML at the time of
malignant transformation.
Tim H. Brümmendorf, Inci Ersöz, Ulrike Hartmann, Kerol Bartolovic, Stefan Balabanov, Alexandra Wahl, Peter Paschka, Sebastian Kreil, Tanja Lahaye, Ute Berger, Harald Gschaidmeier, Carsten Bokemeyer, Rüdiger Hehlmann, Klaus Dietz, Peter M. Lansdorp, Lothar Kanz, and Andreas Hochhaus
Correspondence: Tim H. Brümmendorf, Department of
Hematology and Oncology, University Medical Center II,
Otfried-Müller-Str 10, 72076 Tübingen, Germany; e-mail:
tim.bruemmendorf{at}med.uni-tuebingen.de
Acknowledgments
This study was supported by fortune project No 697-0-0 from the
University of Tübingen, the Sonderforschungsbereich 510 (Teilprojekt A6) of the Deutsche Forschungsgemeinschaft as well as a
grant from the Deutsche Krebshilfe (no. Br 70-2746) and by a grant from the German Ministry of Education and Research (BMBF), Kompetenznetz Akute und chronische Leukämien-01 GI9980/6.
One of the authors (H.G.) has declared a financial interest in a
company whose product was studied in the present work.
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