Elsevier

Leukemia Research

Volume 35, Issue 5, May 2011, Pages e37-e40
Leukemia Research

Letter to the Editor
Concomitant telomere shortening, acquisition of multiple chromosomal aberrations and in vitro resistance to apoptosis in a single case of progressive CLL

https://doi.org/10.1016/j.leukres.2010.11.026Get rights and content

Introduction

Telomeres are repeat DNA sequences (≈10 kb in adult somatic cells), associated with a specific set of proteins at the ends of eukaryotic chromosomes. Telomere maintenance is crucial for genome integrity and for the regulation of cellular proliferative activity. Telomeres progressively shorten in somatic cells which ultimately limits the number of cell divisions but this shortening is prevented from reaching critical levels in cancer cells (rev. [1]). The mean telomere length is a new prognostic marker in chronic lymphocytic leukaemia (CLL) as the aggressive form of the disease has shorter telomeres than the indolent form [2], [3].

CLL is a malignancy due to an imbalance between cell death and proliferation. Clinically, it is a highly heterogeneous and unpredictable disease (rev. [4]). We demonstrated previously that a subgroup of CLL cells is resistant to DNA damage-induced apoptosis in vitro [5]. This new classification is of particular interest given that the first line treatment of CLL is based on alkylating agents (chlorambucil) or nucleoside analogues (fludarabine) whose pharmacological action is DNA damage. We have further demonstrated that telomeric dysfunction is associated with the inability of CLL cells to activate apoptotic cell death following DNA damage. This dysfunction is characterised by telomere shortening and an aberrant telomeric structure [6]. In parallel, 3′ overhang shortening, telomere recognition by proteins involved in the DNA damage response, and telomere deletions occur simultaneously in resistant CLL cells [7].

Here we describe for the first time the CLL case in which clinical and biological phenomena such as disease progression, telomeric dysfunction and an acquisition of resistance to DNA damage-induced apoptosis in arised simultaneously.

Section snippets

Case report

With respect to DNA damage-induced apoptosis in vitro, leukemic cells from this patient had been found to be sensitive in 2000 (>60% of apoptosis after genotoxic stress) but were resistant in 2007 (the rate of apoptosis after radiation could be attributed to normal spontaneous programmed cell death; Fig. 1A). At diagnosis, this patient exhibited markers of a poor prognosis in 2000 (del 11q22 and unmutated IGHV status) but nevertheless survived for a relatively long period (10 years), which is

Results and discussion

To investigate the simultaneous appearance of telomeric dysfunction and the onset resistance to DNA damage-induced apoptosis in CLL cells, we analysed three cell samples from this patient: a specimen that had been isolated in 2000 when the cells were classified as sensitive to DNA damage-induced apoptosis (>60% of the cells became apoptotic after a genotoxic treatment); a sample from 2006 in which the cells were less sensitive to DNA damaging agents (≈30%); and cells harvested in 2007 that

Conflict of Interest

The authors reported no potential conflicts of interest.

Acknowledgements

Authors thank the leukaemic patient who voluntarily participated in this study. This work was supported by Association pour la Recherche sur le Carner (ARC) and CEA.

Contributions. HMB, FNK, TB and JD designed research, interpreted data and wrote the manuscript. TB performed research and analysed data. HMB and FNK recruited and followed-up clinical evolution of the patient.

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1

National Institute for Medical Research, Jean Langhorne's Lab, London, UK.

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