Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis

Lin, Thet Thet, Letsolo, Boitelo Theresiah, Robinson, Rhiannon Elizabeth, Rowson, Janet Maud, Pratt, Guy, Hewamana, Saman, Fegan, Christopher Daniel ORCID: https://orcid.org/0000-0001-9685-0621, Pepper, Christopher John and Baird, Duncan Martin ORCID: https://orcid.org/0000-0001-8408-5467 2010. Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis. Blood 116 (11) , pp. 1899-1907. 10.1182/blood-2010-02-272104

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Abstract

We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukaemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from individuals with the shortest telomeres revealed limited numbers of repeats at the breakpoint, sub-telomeric deletion and microhomology. Array-CGH analysis of individuals displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. The telomere dynamics observed in CLL B-cells were indistinguishable from that observed in cells undergoing crisis in culture following abrogation of the p53 pathway. Taken together our data support the concept that telomere erosion and subsequent telomere fusion is critical in the progression of CLL, and that this paradigm may extend to other malignancies.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RB Pathology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	American Society of Hematology
ISSN:	0006-4971
Last Modified:	06 Nov 2022 13:58
URI:	https://orca.cardiff.ac.uk/id/eprint/28349

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