Role of Telomeres in Onco-Hematology

Telomeres are protective structure located on the endings of human chromosomes, that prevent translocation and progressive shortening of DNA coding sequences. Several studies showed that telomeres are involved in regulation of cell lifespan and proliferative potential. The role of telomeres in oncogenesis is still a matter of active investigation. Recently, some papers identified telomere length alterations in patients affected by Chronic Myeloid Leukemia and Myelofibrosis. My research activity focused on the relation between telomere length and the outcome of patients with Chronic Myeloid Leukemia and Myelofibrosis. My aim was to investigate new therapeutic targets and outcome predictive factors. In particular, I pursued two research lines: first, I tried to evaluate the role of telomeres as biomarker to discriminate patients with Chronic Myeloid Leukemia that could safely stop tyrosine kinase therapy. Next, I investigated the relation between telomere length and response to Ruxolitinib, a recently approved JAK-STAT inhibitor, who proved to be highly beneficial to high-risk patients with Myelofibrosis. I enrolled a population of 32 patients affected by Chronic Myeloid Leukemia who discontinued imatinib after achieving complete molecular remission and 32 age-sex-matched controls, for whom was possible to evaluate telomere length. I performed the clinical management of these patients and the data analysis. The relative telomere length (RTL) was determined by q-PCR as the telomere to single copy gene (36B4) ratio normalized to a reference sample (K-562 DNA). Age-corrected RTL (acRTL) was also obtained. The 36-month probability of treatment-free remission (TFR) was 59.4 %. TFR patients showed shorter acRTL compared to relapsed (mean ± SD = 0.01 ± 0.14 vs 0.20 ± 0.21; p = 0.01). TFR was significantly higher in CML patients with acRTL ≤0.09 (78.9 vs 30.8 %, p = 0.002). These findings indicate that telomere length seems to be related to treatment free remission in CML patients, and may be a useful biomarker to select patients candidate to treatment interruption. Next, I enrolled a population of 11 patients affected by Myelofibrosis, eligible to Ruxolitinib treatment, for whom was possible to evaluate telomere length before and after a median of 1000 days of Ruxolitinib therapy. I performed the clinical management of this cohort, and the data analysis. The RTL was determined as stated before. Related samples Wilcoxon signed-rank test performed before treatment with Ruxolitinib showed that the mean RTL was shorter in patients compared with age-and sex-matched healthy controls (1.08 vs 1.26, respectively; P = 0.09). The most interesting finding was that Mann-Whitney Utest showed shorter acRTL in MF patients with high IPSS compared to patients with intermediate-2 IPSS (mean ± SD = 1.016 ± 0.22 vs 1.34 ± 0.14; p= 0.03); furthermore, median RTL increased significantly (1.30 vs 1.08; p = 0.018), showing overlapping values with the healthy controls. Median RTL elongation from baseline was 15%. These findings seem to indicate that telomeres are involved in the dynamics of Myelofibrosis evolution and treatment response, and may be a possible therapeutic target in these patients. In conclusion, this research highlights some interesting points of the complex relation between telomere length and outcome of patients treated for Chronic Myeloid Leukemia and Myelofibrosis. If confirmed, these findings will be a useful advance in understanding response to treatment in these populations