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Michael Uhlin - One of the best experts on this subject based on the ideXlab platform.
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Assessment of TREC, KREC and Telomere length in long-term survivors after allogeneic HSCT: the role of GvHD and graft source and evidence for Telomere Homeostasis in young recipients
Bone marrow transplantation, 2017Co-Authors: Ahmed Gaballa, Anna Norberg, Arwen Stikvoort, J Mattsson, Berit Sundberg, Mehmet Uzunel, Mats Remberger, Michael UhlinAbstract:Reconstitution of the adaptive immune system following allogeneic hematopoietic stem cell transplantation is crucial for beneficial outcome and is affected by several factors, such as GvHD and graft source. The impact of these factors on immune reconstitution has been thoroughly investigated during the early phase after transplantation. However, little is known about their long-term effect. Similarly, leukocyte Telomere length (TL) shortening has been reported shortly after transplantation. Nevertheless, whether TL shortening continues in long-term aspect is still unsettled. Here, we assessed T-cell receptor excision circle (TREC), kappa deleting recombination excision circle (KREC) and leukocyte TL in recipients and donors several years post transplantation (median 17 years). Our analysis showed that, recipients who received bone marrow (BM) as the graft source have higher levels of both TREC and KREC. Also, chronic GvHD affected TREC levels and TL but not KREC levels. Finally, we show that recipient's TL was longer than respective donors in a group of young age recipients with high KREC levels. Our results suggest that BM can be beneficial for long-term adaptive immune recovery. We also present supporting evidence for recipient Telomere Homeostasis, especially in young age recipients, rather than Telomere shortening.
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Assessment of TREC, KREC and Telomere length in long term survivors after allogeneic HSCT : the role of GVHD and graft source and evidence for Telomere Homeostasis in young recipients
Scandinavian Journal of Immunology, 2017Co-Authors: Ahmed Gaballa, Anna Norberg, Arwen Stikvoort, J Mattsson, Berit Sundberg, Mehmet Uzunel, Mats Remberger, Michael UhlinAbstract:Assessment of TREC, KREC and Telomere length in long term survivors after allogeneic HSCT : the role of GVHD and graft source and evidence for Telomere Homeostasis in young recipients
Peter M. Lansdorp - One of the best experts on this subject based on the ideXlab platform.
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Defects in Lymphocyte Telomere Homeostasis Contribute to Cellular Immune phenotype in Cartilage-Hair Hypoplasia
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Geraldine Aubert, Peter M. Lansdorp, Kevin A. Strauss, Nicholas L. RiderAbstract:BACKGROUND: Mutations in the lncRNA RNase component of the Mitochondrial RNA Processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well known "Telomere disorder". RMRP binds the telomerase reverse transcriptase protein TERT in some cell lines, raising the possibility that RMRP may play a role in Telomere biology. OBJECTIVE: We sought to determine if a Telomere phenotype is present in immune cells from individuals with CHH and explore mechanisms underlying these observations. METHODS: We assessed the proliferative capacity and Telomere length using flow-FISH (in situ hybridization and flow cytometry) of primary lymphocytes from CHH, carrier relatives and control individuals. The role of telomerase holoenzyme components gene expression and activity were assessed by quantitative PCR and Telomere repeat amplification assay (TRAP) from PBMC and enriched lymphocyte cultures. RESULTS: Lymphocyte cultures from CHH individuals display growth defects in vitro, consistent with an immune deficiency cellular phenotype. Here we show that Telomere length and telomerase activity are impaired in primary lymphocyte subsets from cartilage-hair hypoplasia patients. Notably, telomerase activity is affected in a gene dose dependent manner when comparing heterozygote RMRP carriers to individuals with CHH. Telomerase deficiency in CHH is not mediated by abnormal telomerase gene transcript levels relative to endogenous genes. CONCLUSION: These findings suggest that Telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism.
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Defects in lymphocyte Telomere Homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia.
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Geraldine Aubert, Peter M. Lansdorp, Kevin A. Strauss, Nicholas L. RiderAbstract:Background Mutations in the long noncoding RNA RNase component of the mitochondrial RNA processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well-known "Telomere disorder." RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might play a role in Telomere biology. Objective We sought to determine whether a Telomere phenotype is present in immune cells from patients with CHH and explore mechanisms underlying these observations. Methods We assessed proliferative capacity and Telomere length using flow–fluorescence in situ hybridization ( in situ hybridization and flow cytometry) of primary lymphocytes from patients with CHH, carrier relatives, and control subjects. The role of telomerase holoenzyme components in gene expression and activity were assessed by using quantitative PCR and the Telomere repeat amplification protocol from PBMCs and enriched lymphocyte cultures. Results Lymphocyte cultures from patients with CHH display growth defects in vitro , which is consistent with an immune deficiency cellular phenotype. Here we show that Telomere length and telomerase activity are impaired in primary lymphocyte subsets from patients with CHH. Notably, telomerase activity is affected in a gene dose-dependent manner when comparing heterozygote RMRP carriers with patients with CHH. Telomerase deficiency in patients with CHH is not mediated by abnormal telomerase gene transcript levels relative to those of endogenous genes. Conclusion These findings suggest that Telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism.
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Defects in lymphocyte Telomere Homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia.
The Journal of allergy and clinical immunology, 2017Co-Authors: Geraldine Aubert, Peter M. Lansdorp, Kevin A. Strauss, Nicholas L. RiderAbstract:Mutations in the long noncoding RNA RNase component of the mitochondrial RNA processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well-known "Telomere disorder." RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might play a role in Telomere biology. We sought to determine whether a Telomere phenotype is present in immune cells from patients with CHH and explore mechanisms underlying these observations. We assessed proliferative capacity and Telomere length using flow-fluorescence in situ hybridization (in situ hybridization and flow cytometry) of primary lymphocytes from patients with CHH, carrier relatives, and control subjects. The role of telomerase holoenzyme components in gene expression and activity were assessed by using quantitative PCR and the Telomere repeat amplification protocol from PBMCs and enriched lymphocyte cultures. Lymphocyte cultures from patients with CHH display growth defects in vitro, which is consistent with an immune deficiency cellular phenotype. Here we show that Telomere length and telomerase activity are impaired in primary lymphocyte subsets from patients with CHH. Notably, telomerase activity is affected in a gene dose-dependent manner when comparing heterozygote RMRP carriers with patients with CHH. Telomerase deficiency in patients with CHH is not mediated by abnormal telomerase gene transcript levels relative to those of endogenous genes. These findings suggest that Telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Collapse of Telomere Homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes.
PLoS genetics, 2012Co-Authors: Geraldine Aubert, Gabriela M. Baerlocher, Irma Vulto, Steven S.s. Poon, Peter M. LansdorpAbstract:Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain Telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the Telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average Telomere length in granulocytes and lymphocytes at any given age. The average Telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte Telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (hTERT) or the telomerase RNA template (hTERC) gene displayed striking and comparable Telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte Telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain Telomere Homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall Telomere shortening, are nevertheless crucial to maintain Telomere Homeostasis with age.
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prolonged self renewal activity unmasks telomerase control of Telomere Homeostasis and function of mouse hematopoietic stem cells
Blood, 2011Co-Authors: Sanja Sekulovic, Irma Vulto, Peter M. Lansdorp, Vala Gylfadottir, Maura Gasparetto, Yasmine Even, Christy Brookes, Clayton Smith, Connie J Eaves, Fabio M V RossiAbstract:Strategies for expanding hematopoietic stem cells (HSCs) could have significant utility for transplantation-based therapies. However, deleterious consequences of such manipulations remain unknown. Here we examined the impact of HSC self-renewal divisions in vitro and in vivo on their subsequent regenerative and continuing ability to sustain blood cell production in the absence of telomerase. HSC expansion in vitro was obtained using a NUP98-HOXA10hd transduction strategy and, in vivo, using a serial transplant protocol. We observed ∼ 10kb Telomere loss in leukocytes produced in secondary mice transplanted with HSCs regenerated in primary recipients of NUP98-HOXA10hd-transduced and in vitro-expanded Tert−/− HSCs 6 months before. The second generation leukocytes also showed elevated expression of γH2AX (relative to control) indicative of greater accumulating DNA damage. In contrast, significant Telomere shortening was not detected in leukocytes produced from freshly isolated, serially transplanted wild-type (WT) or Tert−/− HSCs, suggesting that HSC replication posttransplant is not limited by Telomere shortening in the mouse. These findings document a role of telomerase in Telomere Homeostasis, and in preserving HSC functional integrity on prolonged self-renewal stimulation.
Ahmed Gaballa - One of the best experts on this subject based on the ideXlab platform.
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Assessment of TREC, KREC and Telomere length in long-term survivors after allogeneic HSCT: the role of GvHD and graft source and evidence for Telomere Homeostasis in young recipients
Bone marrow transplantation, 2017Co-Authors: Ahmed Gaballa, Anna Norberg, Arwen Stikvoort, J Mattsson, Berit Sundberg, Mehmet Uzunel, Mats Remberger, Michael UhlinAbstract:Reconstitution of the adaptive immune system following allogeneic hematopoietic stem cell transplantation is crucial for beneficial outcome and is affected by several factors, such as GvHD and graft source. The impact of these factors on immune reconstitution has been thoroughly investigated during the early phase after transplantation. However, little is known about their long-term effect. Similarly, leukocyte Telomere length (TL) shortening has been reported shortly after transplantation. Nevertheless, whether TL shortening continues in long-term aspect is still unsettled. Here, we assessed T-cell receptor excision circle (TREC), kappa deleting recombination excision circle (KREC) and leukocyte TL in recipients and donors several years post transplantation (median 17 years). Our analysis showed that, recipients who received bone marrow (BM) as the graft source have higher levels of both TREC and KREC. Also, chronic GvHD affected TREC levels and TL but not KREC levels. Finally, we show that recipient's TL was longer than respective donors in a group of young age recipients with high KREC levels. Our results suggest that BM can be beneficial for long-term adaptive immune recovery. We also present supporting evidence for recipient Telomere Homeostasis, especially in young age recipients, rather than Telomere shortening.
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Assessment of TREC, KREC and Telomere length in long term survivors after allogeneic HSCT : the role of GVHD and graft source and evidence for Telomere Homeostasis in young recipients
Scandinavian Journal of Immunology, 2017Co-Authors: Ahmed Gaballa, Anna Norberg, Arwen Stikvoort, J Mattsson, Berit Sundberg, Mehmet Uzunel, Mats Remberger, Michael UhlinAbstract:Assessment of TREC, KREC and Telomere length in long term survivors after allogeneic HSCT : the role of GVHD and graft source and evidence for Telomere Homeostasis in young recipients
Kenkichi Masutomi - One of the best experts on this subject based on the ideXlab platform.
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A non-canonical function of zebrafish telomerase reverse transcriptase is required for developmental hematopoiesis.
PloS one, 2008Co-Authors: Shintaro Imamura, Junzo Uchiyama, Eriko Koshimizu, Jun-ichi Hanai, Christina Raftopoulou, Ryan D. Murphey, Peter E. Bayliss, Yoichi Imai, Caroline E. Burns, Kenkichi MasutomiAbstract:Although it is clear that telomerase expression is crucial for the maintenance of Telomere Homeostasis, there is increasing evidence that the TERT protein can have physiological roles that are independent of this central function. To further examine the role of telomerase during vertebrate development, the zebrafish telomerase reverse transcriptase (zTERT) was functionally characterized. Upon zTERT knockdown, zebrafish embryos show reduced telomerase activity and are viable, but develop pancytopenia resulting from aberrant hematopoiesis. The blood cell counts in TERT-depleted zebrafish embryos are markedly decreased and hematopoietic cell differentiation is impaired, whereas other somatic lineages remain morphologically unaffected. Although both primitive and definitive hematopoiesis is disrupted by zTERT knockdown, the Telomere lengths are not significantly altered throughout early development. Induced p53 deficiency, as well as overexpression of the anti-apoptotic proteins Bcl-2 and E1B-19K, significantly relieves the decreased blood cells numbers caused by zTERT knockdown, but not the impaired blood cell differentiation. Surprisingly, only the reverse transcriptase motifs of zTERT are crucial, but the telomerase RNA-binding domain of zTERT is not required, for rescuing complete hematopoiesis. This is therefore the first demonstration of a non-canonical catalytic activity of TERT, which is different from “authentic” telomerase activity, is required for during vertebrate hematopoiesis. On the other hand, zTERT deficiency induced a defect in hematopoiesis through a potent and specific effect on the gene expression of key regulators in the absence of Telomere dysfunction. These results suggest that TERT non-canonically functions in hematopoietic cell differentiation and survival in vertebrates, independently of its role in Telomere Homeostasis. The data also provide insights into a non-canonical pathway by which TERT functions to modulate specification of hematopoietic stem/progenitor cells during vertebrate development. (276 words)
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the telomerase reverse transcriptase regulates chromatin state and dna damage responses
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Kenkichi Masutomi, Peter M. Lansdorp, Richard Possemato, Judy M Y Wong, Jennifer L Currier, Zuzana Tothova, Judith Manola, Shridar Ganesan, Kathleen Collins, William C HahnAbstract:Constitutive expression of telomerase prevents senescence and crisis by maintaining Telomere Homeostasis. However, recent evidence suggests that telomerase is dynamically regulated in normal cells and also contributes to transformation independently of net Telomere elongation. Here, we show that suppression of the telomerase catalytic subunit [human telomerase reverse transcriptase (hTERT)] expression abrogates the cellular response to DNA double strand breaks. Loss of hTERT does not alter short-term Telomere integrity but instead affects the overall configuration of chromatin. Cells lacking hTERT exhibit increased radiosensitivity, diminished capacity for DNA repair, and fragmented chromosomes, demonstrating that loss of hTERT impairs the DNA damage response.
Geraldine Aubert - One of the best experts on this subject based on the ideXlab platform.
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Defects in lymphocyte Telomere Homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia.
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Geraldine Aubert, Peter M. Lansdorp, Kevin A. Strauss, Nicholas L. RiderAbstract:Background Mutations in the long noncoding RNA RNase component of the mitochondrial RNA processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well-known "Telomere disorder." RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might play a role in Telomere biology. Objective We sought to determine whether a Telomere phenotype is present in immune cells from patients with CHH and explore mechanisms underlying these observations. Methods We assessed proliferative capacity and Telomere length using flow–fluorescence in situ hybridization ( in situ hybridization and flow cytometry) of primary lymphocytes from patients with CHH, carrier relatives, and control subjects. The role of telomerase holoenzyme components in gene expression and activity were assessed by using quantitative PCR and the Telomere repeat amplification protocol from PBMCs and enriched lymphocyte cultures. Results Lymphocyte cultures from patients with CHH display growth defects in vitro , which is consistent with an immune deficiency cellular phenotype. Here we show that Telomere length and telomerase activity are impaired in primary lymphocyte subsets from patients with CHH. Notably, telomerase activity is affected in a gene dose-dependent manner when comparing heterozygote RMRP carriers with patients with CHH. Telomerase deficiency in patients with CHH is not mediated by abnormal telomerase gene transcript levels relative to those of endogenous genes. Conclusion These findings suggest that Telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism.
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Defects in Lymphocyte Telomere Homeostasis Contribute to Cellular Immune phenotype in Cartilage-Hair Hypoplasia
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Geraldine Aubert, Peter M. Lansdorp, Kevin A. Strauss, Nicholas L. RiderAbstract:BACKGROUND: Mutations in the lncRNA RNase component of the Mitochondrial RNA Processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well known "Telomere disorder". RMRP binds the telomerase reverse transcriptase protein TERT in some cell lines, raising the possibility that RMRP may play a role in Telomere biology. OBJECTIVE: We sought to determine if a Telomere phenotype is present in immune cells from individuals with CHH and explore mechanisms underlying these observations. METHODS: We assessed the proliferative capacity and Telomere length using flow-FISH (in situ hybridization and flow cytometry) of primary lymphocytes from CHH, carrier relatives and control individuals. The role of telomerase holoenzyme components gene expression and activity were assessed by quantitative PCR and Telomere repeat amplification assay (TRAP) from PBMC and enriched lymphocyte cultures. RESULTS: Lymphocyte cultures from CHH individuals display growth defects in vitro, consistent with an immune deficiency cellular phenotype. Here we show that Telomere length and telomerase activity are impaired in primary lymphocyte subsets from cartilage-hair hypoplasia patients. Notably, telomerase activity is affected in a gene dose dependent manner when comparing heterozygote RMRP carriers to individuals with CHH. Telomerase deficiency in CHH is not mediated by abnormal telomerase gene transcript levels relative to endogenous genes. CONCLUSION: These findings suggest that Telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism.
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Defects in lymphocyte Telomere Homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia.
The Journal of allergy and clinical immunology, 2017Co-Authors: Geraldine Aubert, Peter M. Lansdorp, Kevin A. Strauss, Nicholas L. RiderAbstract:Mutations in the long noncoding RNA RNase component of the mitochondrial RNA processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well-known "Telomere disorder." RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might play a role in Telomere biology. We sought to determine whether a Telomere phenotype is present in immune cells from patients with CHH and explore mechanisms underlying these observations. We assessed proliferative capacity and Telomere length using flow-fluorescence in situ hybridization (in situ hybridization and flow cytometry) of primary lymphocytes from patients with CHH, carrier relatives, and control subjects. The role of telomerase holoenzyme components in gene expression and activity were assessed by using quantitative PCR and the Telomere repeat amplification protocol from PBMCs and enriched lymphocyte cultures. Lymphocyte cultures from patients with CHH display growth defects in vitro, which is consistent with an immune deficiency cellular phenotype. Here we show that Telomere length and telomerase activity are impaired in primary lymphocyte subsets from patients with CHH. Notably, telomerase activity is affected in a gene dose-dependent manner when comparing heterozygote RMRP carriers with patients with CHH. Telomerase deficiency in patients with CHH is not mediated by abnormal telomerase gene transcript levels relative to those of endogenous genes. These findings suggest that Telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Collapse of Telomere Homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes.
PLoS genetics, 2012Co-Authors: Geraldine Aubert, Gabriela M. Baerlocher, Irma Vulto, Steven S.s. Poon, Peter M. LansdorpAbstract:Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain Telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the Telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average Telomere length in granulocytes and lymphocytes at any given age. The average Telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte Telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (hTERT) or the telomerase RNA template (hTERC) gene displayed striking and comparable Telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte Telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain Telomere Homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall Telomere shortening, are nevertheless crucial to maintain Telomere Homeostasis with age.
