Targeting Telomere Biology in Acute Lymphoblastic Leukemia.

Axel Karow,Ingrid Helsen,Roland A Ammann,Daniela Steiner,Jochen Roessler,Alexander Röth,Mutlu Kartal-Kaess,Tobias M Dantonello,Nicole Preising,Monika Haubitz,Elisabeth Oppliger Leibundgut,Gabriela M Baerlocher

doi:10.3390/ijms22136653

Abstract

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.

Highlights

Telomerase has become a target of novel therapies, and recent preclinical and clinical studies have demonstrated the efficacy of the competitive telomerase inhibitor imetelstat in hematologic malignancies, in particular, myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia [13,14,15,16]
We combined the exploration of differences in telomere biology in normal versus leukemic cells within a clinical study of pediatric patients with acute lymphoblastic leukemia (ALL), with the investigation of ex vivo effects of the telomerase inhibitor imetelstat on primary B-ALL
The lower lymphoblast count found in the BM and higher values in the peripheral blood (PB) of high-risk ALL patients could be due to lymphoblasts that lost adhesion molecules and migrated into the circulation and other lymphatic tissues, as has been described in solid tumors and leukemia alike [20,21]

Summary

Introduction

A number of genomic studies have facilitated the further subclassification of pediatric and adult acute lymphoblastic leukemia (ALL) and provided deeper insight creativecommons.org/licenses/by/ 4.0/). Into the interplay of genetic alterations and their possible role in disease pathogenesis [1,2]. Some of these alterations bear significant implications for the diagnosis, risk stratification, and therapeutic approach of childhood and adult ALL [3,4]. Most human cancer cells reactivate telomerase, thereby compensating for the loss of telomere repeats with cellular replication, enabling immortality [5,6]. Telomerase has become a target of novel therapies, and recent preclinical and clinical studies have demonstrated the efficacy of the competitive telomerase inhibitor imetelstat in hematologic malignancies, in particular, myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia [13,14,15,16]

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Conclusion