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Article

Targeting Telomere Biology in Acute Lymphoblastic Leukemia

1
Department of Pediatrics, Division of Pediatric Hematology/Oncology, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
2
Pediatric Hematology/Oncology, Department of BioMedical Research (DBMR), University of Bern, 3012 Bern, Switzerland
3
Laboratory for Hematopoiesis and Molecular Genetics, Experimental Hematology, Department of BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
4
Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
5
Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 47147 Essen, Germany
6
Kinderaerzte KurWerk, 3400 Burgdorf, Switzerland
*
Author to whom correspondence should be addressed.
Current affiliation: Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
The authors share first authorship.
Academic Editors: Simona Soverini and Gabriele Saretzki
Int. J. Mol. Sci. 2021, 22(13), 6653; https://doi.org/10.3390/ijms22136653
Received: 28 April 2021 / Revised: 2 June 2021 / Accepted: 14 June 2021 / Published: 22 June 2021
(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2020)
Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment. View Full-Text
Keywords: acute lymphoblastic leukemia (ALL); clonal expansion; replicative history; telomere length; telomerase activity; prognostic markers; telomerase inhibitor; imetelstat acute lymphoblastic leukemia (ALL); clonal expansion; replicative history; telomere length; telomerase activity; prognostic markers; telomerase inhibitor; imetelstat
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MDPI and ACS Style

Karow, A.; Haubitz, M.; Oppliger Leibundgut, E.; Helsen, I.; Preising, N.; Steiner, D.; Dantonello, T.M.; Ammann, R.A.; Roessler, J.; Kartal-Kaess, M.; Röth, A.; Baerlocher, G.M. Targeting Telomere Biology in Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2021, 22, 6653. https://doi.org/10.3390/ijms22136653

AMA Style

Karow A, Haubitz M, Oppliger Leibundgut E, Helsen I, Preising N, Steiner D, Dantonello TM, Ammann RA, Roessler J, Kartal-Kaess M, Röth A, Baerlocher GM. Targeting Telomere Biology in Acute Lymphoblastic Leukemia. International Journal of Molecular Sciences. 2021; 22(13):6653. https://doi.org/10.3390/ijms22136653

Chicago/Turabian Style

Karow, Axel, Monika Haubitz, Elisabeth Oppliger Leibundgut, Ingrid Helsen, Nicole Preising, Daniela Steiner, Tobias M. Dantonello, Roland A. Ammann, Jochen Roessler, Mutlu Kartal-Kaess, Alexander Röth, and Gabriela M. Baerlocher. 2021. "Targeting Telomere Biology in Acute Lymphoblastic Leukemia" International Journal of Molecular Sciences 22, no. 13: 6653. https://doi.org/10.3390/ijms22136653

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