Telomere length and telomerase activity in the BCR-ABL-transformed murine Pro-B cell line BaF3 is unaffected by treatment with imatinib.
OBJECTIVE
Imatinib mesylate is a novel tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome positive (Ph+) leukemia and other malignancies. In previous studies, we found significant telomere shortening in Ph+ cells from patients with chronic myeloid leukemia (CML). Interestingly, imatinib treatment was found to lead to a normalization of previously shortened telomere length in CML patients. Based on recent reports demonstrating that c-ABL phosphorylates hTERT and thereby inhibits hTERT activity, a direct effect of imatinib on hTERT activity leading to telomere elongation in BCR-ABL-positive cells has been proposed by others. Such an effect could be of potential importance for telomere maintenance in Ph+ cells by facilitating clonal selection and progression of the disease to blast crisis.


METHODS
We investigated the impact of imatinib on telomere length and telomerase activity of the interleukin-3 (IL-3)-dependent murine pro-B cell line BaF3 and the BCR-ABL-positive, IL-3-independent transfectant BaF3p185 in vitro.


RESULTS
When BaF3 and BaF3p185 cells were treated with imatinib (the latter being rescued with IL-3), no effect on either telomerase activity or telomere length was observed. These findings can be explained by the cytoplasmatic localization of BCR-ABL found in BaF3p185 as compared to the nuclear localization of telomerase (and c-ABL).


CONCLUSIONS
As opposed to recent reports for c-ABL, we do not see evidence for a functional interaction between BCR-ABL and hTERT in this model system arguing against imatinib-mediated upregulation of hTERT as a crucial factor for clonal selection and disease progression of CML.
Hartmann
Ulrike
U
Department of Hematology and Oncology, University of Tübingen, Tübingen, Germany.
Balabanov
Stefan
S
Ziegler
Patrick
P
Fellenberg
Jörg
J
van der Kuip
Heiko
H
Duyster
Justus
J
Lipp
Hans-Peter
HP
Bokemeyer
Carsten
C
Kanz
Lothar
L
Brümmendorf
Tim H
TH
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D003470:Culture Media; D005455:Fluorescent Antibody Technique; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere
D001549:Benzamides; D003470:Culture Media; D007377:Interleukin-3; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D019098:Telomerase