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Leukemia. 2019 Mar 25. doi: 10.1038/s41375-019-0446-4. [Epub ahead of print]

Short telomeres are associated with inferior outcome, genomic complexity, and clonal evolution in chronic lymphocytic leukemia.

Author information

1
Department of Internal Medicine III, Ulm University, Ulm, Germany.
2
Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
3
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, USA.
4
New York Genome Center, New York, NY, USA.
5
Department I for Internal Medicine and Centre for Integrated Oncology, University of Cologne, Cologne, Germany.
6
Broad Institute, Cambridge, MA, USA.
7
Mechanisms of Leukemogenesis, DKFZ, Heidelberg, Germany.
8
Department II of Internal Medicine, University Hospital of Schleswig-Holstein, Kiel, Germany.
9
Division of Internal Medicine, Medical Clinic III, Rostock University Medical Center, Rostock, Germany.
10
Department of Medicine I, Division of Hematology and Hemostaeology, Medical University of Vienna, Vienna, Austria.
11
Division of Hematology, University Hospital Zürich, Zürich, Switzerland.
12
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
13
Klinikum Schwabing, Academic Teaching Hospital of University of Munich, Munich, Germany.
14
Department of Internal Medicine III, Ulm University, Ulm, Germany. stephan.stilgenbauer@uniklinik-ulm.de.

Abstract

Telomere length in chronic lymphocytic leukemia (CLL) has been shown to be of prognostic importance, but the analyses have largely been executed on heterogeneous patient cohorts outside of clinical trials. In the present study, we performed a comprehensive analysis of telomere length associations in the well characterized CLL8 trial (n = 620) of the German CLL study group, with validation in a representative cohort of the CLL4 trial (n = 293). Absolute telomere length was analyzed using quantitative-PCR. Apart from identifying associations of short telomere length with adverse prognostic factors and survival, the study identified cases with 17p- and 11q- associated with TP53 and ATM loss, respectively, to have the shortest telomeres, even when these aberrations were present in small subclones. Thus, telomere shortening may precede acquisition of the high-risk aberrations, contributing to disease evolution. In line with this, telomere shortening was associated with an increase in genomic complexity as well as clonal evolution, highlighting its importance as a biomarker especially in monitoring disease progression in non-high-risk CLL.

PMID:
30911113
DOI:
10.1038/s41375-019-0446-4

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