Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide

Göhring, Gudrun; Lange, Kathrin; Hofmann, Winfried; Nielsen, Kirsten; Hellström‐Lindberg, Eva; Roy, Laurent-Olivier; Morgan, Michael; Kreipe, Hans-Heinrich; Büsche, Guntram; Giagounidis, Aristoteles; Schlegelberger, Brigitte

doi:10.1038/leu.2011.193

Cited by 24 publications

(19 citation statements)

References 9 publications

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“…In line with our findings, Lange et al observed accelerated telomere shortening in patients with del (5q)MDS [26]. Furthermore, Göhring et al retrospectively compared two different cohorts of del (5q) MDS patients (n = 7 patients each), that either did or did not undergo transformation towards AML under lenalidomide treatment [27]. They reported accelerated telomere shortening in patients, that later underwent disease progression under lenalidomide treatment as compared to patients with stable remissions.…”

Section: Discussionsupporting

confidence: 87%

Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide

et al. 2015

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Section: Discussionsupporting

confidence: 87%

Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide

et al. 2015

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“…Telomere dynamics have been studied to clarify MDS pathophysiology [7111213141516], and a small number of studies have assessed telomere status, telomere length (TL), and telomerase activity (TA) as prognostic factors [71417]. Many of these previous studies used the telomeric repeat amplification protocol (TRAP) assay, Southern blot analysis, or quantitative PCR to evaluate TL [121318].…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of Telomere Lengths and Telomerase Activity in Myelodysplastic Syndrome

Park

Choi

See³

et al. 2017

Ann Lab Med

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BackgroundTelomere shortening is thought to be involved in the pathophysiology of myeloid malignancies, but telomere lengths (TL) during interphase and metaphase in hematopoietic malignancies have not been analyzed. We aimed to assess the TLs of interphase and metaphase cells of MDS and telomerase activity (TA) and to find out prognostic significances of TL and TA.MethodsThe prognostic significance of TA by quantitative PCR and TL by quantitative fluorescence in situ hybridization (QFISH) of interphase nuclei and metaphase chromosome arms of bone marrow cells from patients with MDS were evaluated.ResultsMDS patients had shorter interphase TL than normal healthy donors (P<0.001). Average interphase and metaphase TL were inversely correlated (P=0.013, p arm; P=0.029, q arm), but there was no statistically significant correlation between TA and TL (P=0.258). The progression free survival was significantly shorter in patients with high TA, but the overall survival was not different according to average TA or interphase TL groups. Multivariable Cox analysis showed that old age, higher International Prognostic Scoring System (IPSS) subtypes, transformation to AML, no history of hematopoietic stem cell transplantation and short average interphase TL (<433 TL) as independent prognostic factors for poorer survival (P=0.003, 0.001, 0.005, 0.005, and 0.013, respectively).ConclusionsThe lack of correlation between age and TL, TA, and TL, and the inverse relationship between TL and TA in MDS patients reflect the dysregulation of telomere status and proliferation. As a prognostic marker for leukemia progression, TA may be considered, and since interphase TL has the advantage of automated measurement by QFISH, it may be used as a prognostic marker for survival in MDS.

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“…To gain more information, we subsequently performed follow-up analyses in patients with MDS with an isolated deletion of 5q [62]. At an early time point after initial diagnosis and prior to lenalidomide treatment, patients who had a later disease progression showed significantly shorter telomeres than patients without progression.…”

Section: Telomeresmentioning

confidence: 99%

Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia

Vajen

Thomay

Schlegelberger

2013

Cancers

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Chromosomal instability (CIN) is a characteristic feature of cancer. In this review, we concentrate on mechanisms leading to CIN in myeloid neoplasia, i.e., myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The pathogenesis of myeloid neoplasia is complex and involves genetic and epigenetic alterations. Chromosome aberrations define specific subgroups and guide clinical decisions. Genomic instability may play an essential role in leukemogenesis by promoting the accumulation of genetic lesions responsible for clonal evolution. Indeed, disease progression is often driven by clonal evolution into complex karyotypes. Earlier studies have shown an association between telomere shortening and advanced MDS and underlined the important role of dysfunctional telomeres in the development of genetic instability and cancer. Several studies link chromosome rearrangements and aberrant DNA and histone methylation. Genes implicated in epigenetic control, like DNMT3A, ASXL1, EZH2 and TET2, have been discovered to be mutated in MDS. Moreover, gene-specific hypermethylation correlates highly significantly with the risk score according to the International Prognostic Scoring System. In AML, methylation profiling also revealed clustering dependent on the genetic status. Clearly, genetic instability and clonal evolution are driving forces for leukemic transformation. Understanding the mechanisms inducing CIN will be important for prevention and for novel approaches towards therapeutic interventions.

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Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide

Cited by 24 publications

References 9 publications

Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide

Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide

Dysregulation of Telomere Lengths and Telomerase Activity in Myelodysplastic Syndrome

Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia

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