Abstract
Background: Telomere is a repeatitive sequence at the chromosome end, functioning as a cap, and the length of telomere becomes shortened after each cell devision, eventually going to senescence. Thus, the length of telomere reflects the proliferative capacity of cell and cellular age. Inherited mutation of telomerase gene results in dyskeratosis congenita characterized by telomere shortening and multi-organ stem cell damage. In contrast, stem cells or tumor cells maintain their telomere length by telomerase or alternative telomere lengthening. To investigate the profiles of telomere length among hematologic malignancies, we measured mean telomere length and heterogeneity of telomere length in various hematologic diseases, in comparison with bone marrow failure syndrome, aplastic anemia (AA) and myelodysplastic syndrome (MDS).
Methods: Telomere length was measured by interphase fluorescent in situ hybridization. A total of 153 patients were enrolled; adult MDS (n=53), childhood MDS (n=17), adult AA (n=20), childhood AA (n=46), acute myelogenous leukemia (AML) (n=5), Fanconi anemia (FA) (n=9) and normal control (n=72: normal bone marrow n=36), and normal peripheral blood of children n=36) as a control group. Telomere length was expressed as T/C ratio with adjustment of fluorescence intensity of centromeric signal in chromosome 2. Mean length of telomere and distribution width (SD: standard deviation), were compared to those of normal cells.
Results: Mean telomere length (T/C ratio) was 6.7 (adult AA), 5.9 (childhood AA), 5.0 (adult MDS), 4.4 (childhood MDS), 2.1 in FA, 9.4 in AML, and 19.0 in normal control. Heterogeneity of telomere length expressed as telomere length SD was 4.6 in adult AA, 3.7 in childhood AA, 3.5 in adult MDS, 2.5 in childhood MDS, 1.4 in FA and 4.1 in AML. Cell population below 5th percentile of normal control expressed as percentage among total cells, was 75.0% in adult AA, 4.8% in childhood AA, 12.5% in childhood MDS, 87.0% in adult MDS and 0% in AML. When adult MDS patients were divided into two groups, high (¡Ã average) or low (<average), according to the interphase telomere length among MDS patients. The mean survival time for MDS patients with high telomere length group (n=16) was 53.6 months, and 88.5 months in the low telomere length group (n=37). The overall survival rate of the high telomere length group was higher than the low group with minimal statistical significance by Kaplan Meier survival analysis (P =0.056). The multivariate Cox regression analysis showed that higher age, transformation to acute myeloid leukemia, the IPSS subtypes and the lower interphase telomere length were independent adverse prognostic factors. The hazard ratio for higher age was 1.035, 3.678 for transformation to AML, and 5.169 for the low interphase telomere length).
Conclusion: Short telomere was signature of MDS both in adult and childhood MDS and associated with adverse prognosis. However, telomere length of patients with childhood bone marrow failure syndrome was shortest. Heterogeneity in telomere length of patients with MDS was less prominent than those in patients with AA.
Disclosures
No relevant conflicts of interest to declare.
Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti
