Dynamics of telomere's length and telomerase activity in Philadelphia chromosome negative myeloproliferative neoplasms

Spanoudakis, Emmanouil; Bazdiara, Ioanna; Pantelidou, Despoina; Kotsianidis, Ιoannis; Papadopoulos, Vassilios; Margaritis, Dimitrios; Xanthopoulidis, George; Moustakidis, Eleftherios; Mantzourani, Stamatia; Bourikas, George; Tsatalas, Costas

doi:10.1016/j.leukres.2010.07.042

Cited by 25 publications

(10 citation statements)

References 36 publications

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“…It is believed that the CC genotype promotes TERT transcription, thereby upregulating telomerase activity and maintaining telomere length required for unlimited proliferation of cancer cells [ 18 ]. Similarly, high telomerase activity in the bone marrow of patients with MPN has been reported [ 12 ]. Meanwhile, telomere shortening is well established in MPN myeloid cells [ 11 , 21 , 26 ], likely due to the hyperproliferation of these cells in MPNs.…”

Section: Discussionmentioning

confidence: 79%

“…The aberrant TERT expression confers malignant cells infinite proliferative potential. Similarly, high telomerase activity and TERT expression has been observed in MPNs [ 11 , 12 ]. More recently, a number of studies uncovered an association between the rs2736100 A>C single nucleotide polymorphism (SNP) in the TERT gene and the risk of developing MPNs [ 13 – 17 ].…”

Section: Introductionmentioning

confidence: 94%

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TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations

et al. 2016

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The telomerase reverse transcriptase (TERT) gene rs2736100_C allele has recently been shown to be associated with an increased risk for myeloproliferative neoplasms (MPNs) among Caucasians. However, it is unknown if this association is present in other ethnical populations and whether rs2736100 allele frequencies mirror the incidence of MPNs in a population. Here we genotyped TERT rs2736100 variants in 126 Swedish and 101 Chinese MPN patients and their age-, sex-, and ethnically-matched healthy controls. Healthy Chinese adults had a higher frequency of the A allele and lower frequencies of the C allele compared to Swedish counterparts (57.4 vs 47.0 % for A, 42.6 vs 53.0 % for C, P = 0.006). Both Swedish and Chinese patients harbored significantly higher C allele frequency than their controls (62.7 vs 53.0 % and 57.4 vs 42.6 % for Swedish and Chinese, respectively, P = 0.004). Swedes and Chinese bearing the CC genotype had a significantly increased risk of MPN compared to AA carriers (OR = 2.47; 95 % CI: 1.33–4.57, P = 0.003, for Swedes, and OR = 3.45; 95 % CI: 1.52–7.85, P = 0.005, for Chinese). Further analyses showed that rs2736100_CC was associated with robustly enhanced risk in males only (CC vs AA, OR = 5.11; 95 % CI: 2.19–11.92, P < 0.0001). The CC-carrying MPN patients exhibited significantly higher TERT expression than patients with the AC genotype. Collectively, the rs2736100_C is a risk allele for MPNs in Swedish and Chinese males, and the lower incidence of MPNs in the Chinese population is correlated with a lower rs2736100_C risk allele frequency.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 94%

TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations

et al. 2016

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“…Although these observations could be attributed to the reduced sample size and the different cell fractions analyzed, it has been suggested that imetelstat’s actions in MPN might be due to off-target effects. 40 Alternatively, the response to imetelstat could be influenced by the baseline levels of telomerase, which are reportedly elevated in MPN patients, 41,42 and/or by the epigenetic makeup of the TERT promoter as has been recently shown in AML/myelodysplastic syndromes. 43 Taken together, these observations indicate that TA inhibition might not be the only mode of action of imetelstat and the exact molecular mechanisms underlying its effects on normal and malignant MK require further investigation.…”

Section: Discussionmentioning

confidence: 97%

Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis

Mosoyan

Kraus

et al. 2017

Leukemia

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Imetelstat (GRN163L) is a specific telomerase inhibitor that has demonstrated clinical activity in patients with myeloproliferative neoplasms (MPN) and in patients with solid tumors. The antitumor effects were associated with the development of thrombocytopenia, one of the common side effects observed in patients treated with imetelstat. The events underlying these adverse effects are not apparent. In this report, we investigated the potential mechanisms that account for imetelstat’s beneficial effects in MPN patients and the manner by which imetelstat treatment leads to a reduction in platelet numbers. Using a well-established system of ex vivo megakaryopoiesis, we demonstrated that imetelestat treatment affects normal megakaryocyte (MK) development by exclusively delaying maturation of MK precursor cells. By contrast, additional stages along MPN MK development were affected by imetelstat resulting in reduced numbers of assayable colony-forming unit MK and impaired MK maturation. In addition, treatment with imetelstat inhibited the secretion of fibrogenic growth factors by malignant but not by normal MK. Our results indicate that the delay observed in normal MK maturation may account for imetelstat-induced thrombocytopenia, while the more global effects of imetelstat on several stages along the hierarchy of MPN megakaryopoiesis may be responsible for the favorable clinical outcomes reported in MPN patients.

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“…20 Previously published data on short telomeres and up-regulated telomerase activity in myeloproliferative neoplasms provided additional rationale for conducting the current study. 21,22 Me thods…”

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confidence: 99%

A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis

et al. 2015

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Dynamics of telomere's length and telomerase activity in Philadelphia chromosome negative myeloproliferative neoplasms

Cited by 25 publications

References 36 publications

TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations

TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations

Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis

A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis

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