Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression

Panero, Julieta; Stanganelli, Carmen; Arbelbide, Jorge; Fantl, Dorotea; Kohan, Dana; Rivello, Hernán García; Rabinovich, Gabriel A.; Slavutsky, Irma

doi:10.1016/j.bcmd.2013.10.002

Cited by 21 publications

(23 citation statements)

References 53 publications

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“…The expression profile of shelterin genes in plasma cell disorders have been extensively studied by our group (Table 1) (94,96,97). Our findings showed increased expression of shelterin components in MM compared to MGUS.…”

Section: Plasma Cell Disorderssupporting

confidence: 54%

“…Our findings showed increased expression of shelterin components in MM compared to MGUS. Among the six shelterin subunits, POT1 showed particular significance for being strongly associated with clinical features such as advanced clinical stages, high calcium and β2-microglobulin levels and the presence of bone lesions (96). Moreover, in multivariate analysis, POT1 expression was a significant independent prognostic factor for overall survival as well as the International Staging System.…”

Section: Plasma Cell Disordersmentioning

confidence: 94%

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Telomere protein complexes and their role in lymphoid malignancies

Panero

Santos

Slavutsky³

2017

Front Biosci

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Telomeres are highly regulated and dynamic complexes that protect the genomic DNA and prevent the end of linear chromosomes from being misrecognized as a broken DNA. Due to the end replication problem, telomeres of somatic cells shorten with each cell division, inducing cell senescence. Telomerase is a reverse transcriptase capable of compensating telomere attrition by adding telomere repeats to the ends of chromosomes. Human telomeres are associated with the shelterin complex which consists of six telomere-associated proteins that specifically bind to telomeric DNA. Alterations or removal of individual shelterin components would lead to telomere uncapping and telomere dysfunction, resulting in cellular senescence and transformation to a malignant state. Another complex of multifunctional proteins, named non-shelterin complex, is thought to prevent telomere degradation and facilitate telomerase-based telomere elongation. As telomerase is highly expressed in most human tumor cells, it is considered an attractive target for new therapeutic strategies. In this review, we will summarize the characteristics of telomeres and telomerase in lymphoid malignancies and discuss the role of telomere-associated proteins in these entities.

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Section: Plasma Cell Disorderssupporting

confidence: 54%

Section: Plasma Cell Disordersmentioning

confidence: 94%

Telomere protein complexes and their role in lymphoid malignancies

Panero

Santos

Slavutsky³

2017

Front Biosci

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“…Dysfunctional telomeres may arise either from critically short telomeres or by disruption of the shelterin complex [28]. In some hematologic malignancies, altered expression of shelterin proteins might disrupt the telomere structure, contributing to malignant transformation [13,[28][29][30][31]. Particularly in MCL, to our knowledge, there is only one report on the expression levels of TRF1, TRF2, TNKS, and PIF1 in a limited number of patients (7-8 cases) [30] and no differences in gene expression were found in comparison to lymph nodes.…”

Section: Discussionmentioning

confidence: 99%

“…Gene expression was quantified by qPCR using a LightCycler system (Roche Diagnostics, Mannheim, Germany) with TaqMan methodology. The PCR conditions as well as the sequences of primers and probes were previously described [13,14]. For all targets, the PCR amplification protocol was initiated at 958C for 10 minutes followed by 45 PCR cycles consisting of at 15 sec at 958C followed by 608C for 1 min.…”

Section: Methodsmentioning

confidence: 99%

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

et al. 2016

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Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with poor prognosis. Acquired telomerase reverse transcriptase gene promoter (TERTp) mutations are among the most frequent somatic non-coding mutations in cancers. In this study, the prevalence of TERTp mutations in 24 MCL and 21 other lymphoid neoplasias (oLN) was investigated. Eight MCL samples (33%) carried TERTp mutations, two homozygous and six heterozygous (seven C228T and one C250T), which directly correlated with higher TERT transcription, mitochondrial DNA copy number, and IGHV mutational status in MCL neoplastic cells. TERTp mutations were not found in oLN. TERTp mutations correlated with more lymphoma proliferation and tumor burden, as suggested by the higher number of lymphoma cells circulating in peripheral blood, and tended to associate with longer MCL telomeres, especially in homozygous mutants, although not statistically significant. Telomere-biology genes were overexpressed in MCL cells in comparison to healthy lymphocytes, but were not influenced by mutation status. The findings described for the first time that acquired TERTp mutations are common in MCL but not in other lymphoid neoplasms. It was also demonstrated that TERTp mutations are associated with higher TERT mRNA expression in MCL cells in vivo and higher tumor burden, suggesting these mutations as a driver event in MCL development and progression.

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“…Impaired expression of TRF1, TRF2, and RAP1 is detected in chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) [71][72][73][74][75][76]. Also, abnormal expression of TIN2, ACD/TPP1, and POT1 is involved in chronic lymphocytic leukemia (CLL), aplastic anemia, and multiple myeloma [72,[77][78][79][80]. The attenuation of telomere maintenance is involved in the genetic syndrome dyskeratosis congenita (DC) and its severe form Hoyeraal-Hreidarsson (HH) syndrome [81,82].…”

Section: Abnormalities In Shelterin Gene Related To Hematological Malmentioning

confidence: 99%

The role of telomere binding molecules for normal and abnormal hematopoiesis

Hosokawa

Arai

2018

Int J Hematol

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In order to maintain the homeostasis of the hematopoietic system, hematopoietic stem cells (HSCs) need to be maintained while slowly dividing over their lifetime. However, repeated cell divisions lead to the gradual accumulation of DNA damage and ultimately impair HSC function. Since telomeres are particularly fragile when subjected to replication stress, cells have several defense machinery to protect telomeres. Moreover, HSCs must protect their genome against possible DNA damage, while maintaining telomere length. A group of proteins called the shelterin complex are deeply involved in this two-way role, and it is highly resistant to the replication stress to which HSCs are subjected. Most shelterin-deficient experimental models suffer acute cytotoxicity and severe phenotypes, as each shelterin component is essential for telomere protection. The Tin2 point mutant mice show a dyskeratosis congenita (DC) like phenotype, and the Tpp1 deletion impairs the hematopoietic system. POT1/Pot1a is highly expressed in HSCs and contributes to the maintenance of the HSC pool during in vitro culture. Here, we discuss the role of shelterin molecules in HSC regulation and review current understanding of how these are regulated in the maintenance of the HSC pool and the development of hematological disorders.

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Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression

Cited by 21 publications

References 53 publications

Telomere protein complexes and their role in lymphoid malignancies

Telomere protein complexes and their role in lymphoid malignancies

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

The role of telomere binding molecules for normal and abnormal hematopoiesis

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