Abstract

BackgroundTelomere erosion can lead to genomic instability and cancer progression. It has been suggested that the shortest telomere, not the average telomere length (TL), is critical for cell viability. Some studies have shown shorter TL in myelodysplastic syndrome (MDS) patients but the critically short telomeres, the variability of TL within individual patient has not been evaluated. Thus, we aimed to investigate the TL of MDS patients and assessed the association of TL with recurrent genetic mutations in MDS.MethodsWe measured the TL of bone marrow nucleated cells for diagnostic samples at a single-cell level by quantitative fluorescence in situ hybridization (Q-FISH) for 58 MDS patients and analyzed the minimum, median, average, standard deviation, average of the 0th to 10th percentile TL within a patient, and the proportion of cells with TL that is shorter than the lowest 10th percentile of the normal control (NC). The correlations of TL to clinical parameters, cytogenetic results, and genetic mutations were assessed.ResultsMDS patients showed eroded telomeres and narrow distribution compared to the NC (P < 0.001, P = 0.018, respectively). Patients with mutation showed significantly lesser cells with short TL, below the lowest 10th percentile of the NC (P = 0.017), but no differences in TL were found according to mutations/cytogenetic abnormalities except for CSF3R mutation. However, those patients with a high percentage (≥80 %) of cells with short TL showed poorer overall survival (P = 0.021), and this was an independent prognostic factor, along with TP53, U2AF1 mutation, and high BM blast count (P = 0.044, 0.001, 0.004, 0.012, respectively).ConclusionsThe shortest TL, which determines the fate of the cell, was significantly shorter, and higher burden of cells with short TL were found in MDS, which correlated with poor survival, suggesting the need to measure TL in single cells by Q-FISH.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0287-9) contains supplementary material, which is available to authorized users.

Highlights

  • Telomere erosion can lead to genomic instability and cancer progression

  • The number of cells assessed in the myelodysplastic syndrome (MDS) patients was smaller (P = 0.004) than that assessed in the normal control (NC) due to insufficient nuclei in the patient samples

  • The minimum telomere length (TL), which is thought to be critical in the maintenance of cell survival, did not show prognostic significance in our study, we have found that having a high percentage of cells with short TL compared to NC may be of prognostic significance

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Summary

Introduction

Telomere erosion can lead to genomic instability and cancer progression. It has been suggested that the shortest telomere, not the average telomere length (TL), is critical for cell viability. Some studies have shown shorter TL in myelodysplastic syndrome (MDS) patients but the critically short telomeres, the variability of TL within individual patient has not been evaluated. We aimed to investigate the TL of MDS patients and assessed the association of TL with recurrent genetic mutations in MDS. Shortened telomeres can cause end-to-end fusion of chromosomes, which results in Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell diseases characterized by cytopenia, dysplasia, and ineffective hematopoiesis, with an increased risk of transformation to acute myeloid leukemia (AML) [7, 8]. Due to its predisposition to AML, genomic instability has been studied as the key to the pathogenesis of MDS, and many studies have assessed the telomere components of MDS [9,10,11]. MDS patients have shown a shorter average telomere length (TL) compared. The correlation of TL with various genetic mutations other than telomerase complex genes has not been thoroughly explored [17, 18]

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