Search

Your search keyword '"Lansdorp, P. M."' showing total 406 results
Start Over Author "Lansdorp, P. M."
406 results on '"Lansdorp, P. M."'

1. A non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells

Author

Turkalo, Timothy K, Maffia, Antonio, Schabort, Johannes J, Regalado, Samuel G, Bhakta, Mital, Blanchette, Marco, Spierings, Diana CJ, Lansdorp, Peter M, and Hockemeyer, Dirk

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Stem Cell Research - Nonembryonic - Human, Cancer, Genetics, Stem Cell Research, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Humans, Telomere Homeostasis, Telomere, Cell Differentiation, Telomerase, Pluripotent Stem Cells, X-linked Nuclear Protein
Abstract

Alternative Lengthening of Telomeres (ALT) is an aberrant DNA recombination pathway which grants replicative immortality to approximately 10% of all cancers. Despite this high prevalence of ALT in cancer, the mechanism and genetics by which cells activate this pathway remain incompletely understood. A major challenge in dissecting the events that initiate ALT is the extremely low frequency of ALT induction in human cell systems. Guided by the genetic lesions that have been associated with ALT from cancer sequencing studies, we genetically engineered primary human pluripotent stem cells to deterministically induce ALT upon differentiation. Using this genetically defined system, we demonstrate that disruption of the p53 and Rb pathways in combination with ATRX loss-of-function is sufficient to induce all hallmarks of ALT and results in functional immortalization in a cell type-specific manner. We further demonstrate that ALT can be induced in the presence of telomerase, is neither dependent on telomere shortening nor crisis, but is rather driven by continuous telomere instability triggered by the induction of differentiation in ATRX-deficient stem cells.

Published
2023

2. Multi-platform discovery of haplotype-resolved structural variation in human genomes.

Author

Chaisson, Mark JP, Sanders, Ashley D, Zhao, Xuefang, Malhotra, Ankit, Porubsky, David, Rausch, Tobias, Gardner, Eugene J, Rodriguez, Oscar L, Guo, Li, Collins, Ryan L, Fan, Xian, Wen, Jia, Handsaker, Robert E, Fairley, Susan, Kronenberg, Zev N, Kong, Xiangmeng, Hormozdiari, Fereydoun, Lee, Dillon, Wenger, Aaron M, Hastie, Alex R, Antaki, Danny, Anantharaman, Thomas, Audano, Peter A, Brand, Harrison, Cantsilieris, Stuart, Cao, Han, Cerveira, Eliza, Chen, Chong, Chen, Xintong, Chin, Chen-Shan, Chong, Zechen, Chuang, Nelson T, Lambert, Christine C, Church, Deanna M, Clarke, Laura, Farrell, Andrew, Flores, Joey, Galeev, Timur, Gorkin, David U, Gujral, Madhusudan, Guryev, Victor, Heaton, William Haynes, Korlach, Jonas, Kumar, Sushant, Kwon, Jee Young, Lam, Ernest T, Lee, Jong Eun, Lee, Joyce, Lee, Wan-Ping, Lee, Sau Peng, Li, Shantao, Marks, Patrick, Viaud-Martinez, Karine, Meiers, Sascha, Munson, Katherine M, Navarro, Fabio CP, Nelson, Bradley J, Nodzak, Conor, Noor, Amina, Kyriazopoulou-Panagiotopoulou, Sofia, Pang, Andy WC, Qiu, Yunjiang, Rosanio, Gabriel, Ryan, Mallory, Stütz, Adrian, Spierings, Diana CJ, Ward, Alistair, Welch, AnneMarie E, Xiao, Ming, Xu, Wei, Zhang, Chengsheng, Zhu, Qihui, Zheng-Bradley, Xiangqun, Lowy, Ernesto, Yakneen, Sergei, McCarroll, Steven, Jun, Goo, Ding, Li, Koh, Chong Lek, Ren, Bing, Flicek, Paul, Chen, Ken, Gerstein, Mark B, Kwok, Pui-Yan, Lansdorp, Peter M, Marth, Gabor T, Sebat, Jonathan, Shi, Xinghua, Bashir, Ali, Ye, Kai, Devine, Scott E, Talkowski, Michael E, Mills, Ryan E, Marschall, Tobias, Korbel, Jan O, Eichler, Evan E, and Lee, Charles

Subjects
Humans, Chromosome Mapping, Genomics, Haplotypes, Genome, Human, Algorithms, Databases, Genetic, INDEL Mutation, Genomic Structural Variation, High-Throughput Nucleotide Sequencing, Whole Genome Sequencing, Genome, Human, Databases, Genetic
Abstract

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (

Published
2019

3. Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51

Author

Heijink, Anne Margriet, Stok, Colin, Porubsky, David, Manolika, Eleni Maria, de Kanter, Jurrian K., Kok, Yannick P., Everts, Marieke, de Boer, H. Rudolf, Audrey, Anastasia, Bakker, Femke J., Wierenga, Elles, Tijsterman, Marcel, Guryev, Victor, Spierings, Diana C. J., Knipscheer, Puck, van Boxtel, Ruben, Ray Chaudhuri, Arnab, Lansdorp, Peter M., and van Vugt, Marcel A. T. M.

Published
2022
Full Text
View/download PDF

4. Abstracts from the 3rd Conference on Aneuploidy and Cancer: Clinical and Experimental Aspects

Author

Cornish-Bowden, Athel, Rasnick, David, Heng, Henry H, Horne, Steven, Abdallah, Batoul, Liu, Guo, Ye, Christine J, Bloomfield, Mathew, Vincent, Mark D, Aldaz, C Marcelo, Karlsson, Jenny, Valind, Anders, Jansson, Caroline, Gisselsson, David, Graves, Jennifer A Marshall, Stepanenko, Aleksei A, Andreieva, Svitlana V, Korets, Kateryna V, Mykytenko, Dmytro O, Huleyuk, Nataliya L, Baklaushev, Vladimir P, Kovaleva, Oksana A, Chekhonin, Vladimir P, Vassetzky, Yegor S, Avdieiev, Stanislav S, Bakker, Bjorn, Taudt, Aaron S, Belderbos, Mirjam E, Porubsky, David, Spierings, Diana CJ, de Jong, Tristan V, Halsema, Nancy, Kazemier, Hinke G, Hoekstra-Wakker, Karina, Bradley, Allan, de Bont, Eveline SJM, van den Berg, Anke, Guryev, Victor, Lansdorp, Peter M, Tatché, Maria Colomé, Foijer, Floris, Liehr, Thomas, Baudoin, Nicolaas C, Nicholson, Joshua M, Soto, Kimberly, Quintanilla, Isabel, Camps, Jordi, Cimini, Daniela, Dürrbaum, M, Donnelly, N, Passerini, V, Kruse, C, Habermann, B, Storchová, Z, Mandrioli, Daniele, Belpoggi, Fiorella, Silbergeld, Ellen K, Perry, Melissa J, Skotheim, Rolf I, Løvf, Marthe, Johannessen, Bjarne, Hoff, Andreas M, Zhao, Sen, SveeStrømme, Jonas M, Sveen, Anita, Lothe, Ragnhild A, Hehlmann, R, Voskanyan, A, Fabarius, A, Böcking, Alfred, Biesterfeld, Stefan, Berynskyy, Leonid, Börgermann, Christof, Engers, Rainer, Dietz, Josef, Fritz, A, Sehgal, N, Vecerova, J, Stojkovicz, B, Ding, H, Page, N, Tye, C, Bhattacharya, S, Xu, J, Stein, G, Stein, J, Berezney, R, Gong, Xue, Grasedieck, Sarah, Swoboda, Julian, Rücker, Frank G, Bullinger, Lars, Pollack, Jonathan R, Roumelioti, Fani-Marlen, Chiourea, Maria, Raftopoulou, Christina, Gagos, Sarantis, Duesberg, Peter, and Bloomfield, Mat

Subjects
Genetics
Published
2017

5. Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals

Author

Levine, Michelle S, Bakker, Bjorn, Boeckx, Bram, Moyett, Julia, Lu, James, Vitre, Benjamin, Spierings, Diana C, Lansdorp, Peter M, Cleveland, Don W, Lambrechts, Diether, Foijer, Floris, and Holland, Andrew J

Subjects
Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Aneuploidy, Animals, Carcinogenesis, Centrosome, Epidermis, Intestinal Neoplasms, Mammals, Mice, Inbred C57BL, Organ Specificity, Protein Serine-Threonine Kinases, Plk4, aneuploidy, centriole, centrosome amplification, genomic instability, mitosis, tumorigenesis, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of cancer remains unclear. Here, we test the consequence of centrosome amplification by creating mice in which centrosome number can be chronically increased in the absence of additional genetic defects. We show that increasing centrosome number elevated tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive aneuploidy and the development of spontaneous tumors in multiple tissues. Tumors arising from centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship among centrosome amplification, genomic instability, and tumor development.

Published
2017

7. Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids

Author

Bolhaqueiro, Ana C. F., Ponsioen, Bas, Bakker, Bjorn, Klaasen, Sjoerd J., Kucukkose, Emre, van Jaarsveld, Richard H., Vivié, Judith, Verlaan-Klink, Ingrid, Hami, Nizar, Spierings, Diana C. J., Sasaki, Nobuo, Dutta, Devanjali, Boj, Sylvia F., Vries, Robert G. J., Lansdorp, Peter M., van de Wetering, Marc, van Oudenaarden, Alexander, Clevers, Hans, Kranenburg, Onno, Foijer, Floris, Snippert, Hugo J. G., and Kops, Geert J. P. L.

Published
2019
Full Text
View/download PDF

10. Pushing the envelope of magnetic tweezer resolution

Author

Lansdorp, Bob M.

Subjects
Engineering, Biophysics, Optics
Abstract

The magnetic tweezer is a single molecule instrument that can measure the extension of biomolecules by tracking tethered probe particles. Due to its experimental simplicity and ability to apply a constant external force to probe particles, the magnetic tweezer is ideally suited to measuring single molecule dynamics under applied tension. In this thesis, I push the resolution of magnetic tweezers to angstrom spatial resolution by using a high-speed camera which can achieve more than 10 kHz temporal resolution.I investigate the fundamental limits to magnetic tweezer resolution from basic principles, and investigate different types of light coherence to arrive on a new choice of light source for the magnetic tweezer: the superluminescent diode. I explore Langevin dynamics of tethered probe particles using the Allan variance, a more intuitive take on thermal fluctuations than the Power Spectral Density. I push the achievable resolution limits by using smaller beads, introduce higher gradient magnets to apply biologically relevant forces on these smaller beads, and introduce a Fourier filter system to achieve higher spatial resolution.

Published
2015

21. Telomeres, aging, and cancer: the big picture

Author

Lansdorp, Peter M.

Abstract

The role of telomeres in human health and disease is yet to be fully understood. The limitations of mouse models for the study of human telomere biology and difficulties in accurately measuring the length of telomere repeats in chromosomes and cells have diverted attention from many important and relevant observations. The goal of this perspective is to summarize some of these observations and to discuss the antagonistic role of telomere loss in aging and cancer in the context of developmental biology, cell turnover, and evolution. It is proposed that both damage to DNA and replicative loss of telomeric DNA contribute to aging in humans, with the differences in leukocyte telomere length between humans being linked to the risk of developing specific diseases. These ideas are captured in the Telomere Erosion in Disposable Soma theory of aging proposed herein.

Published
2022
Full Text
View/download PDF

22. A Growth-Factor Dependent B-Cell Hybridoma

Author

Lansdorp, P. M., Aarden, L. A., Calafat, J., Zeiljemaker, W. P., Clarke, A., editor, Compans, R. W., editor, Cooper, M., editor, Eisen, H., editor, Goebel, W., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M., editor, Vogt, P. K., editor, Wagner, H., editor, Wilson, I., editor, Melchers, Fritz, editor, and Potter, Michael, editor

Published
1986
Full Text
View/download PDF

27. Maintenance of telomere length in AML

Author

Lansdorp, Peter M.

Abstract

The importance of telomere length to human health, aging, and cancer continues to be underappreciated. This review examines some basics of telomere biology and relates how telomere function, telomerase activity, and mutations in TERC or TERT are involved in bone marrow failure, leukemias, and other cancers. Given the challenge to obtain accurate data on telomerase activity and telomere length in specific cell types, the situation in acute myeloid leukemia (AML) remains puzzling. In most cancers, telomerase levels are increased after cells have encountered a “telomere crisis,” which is typically associated with poor prognosis. Cells emerging from “telomere crisis” have defective DNA damage responses, resulting, for example, from loss of p53. Such cells often express elevated telomerase levels as a result of point mutations in the TERT promoter or amplification of the TERT gene. While telomeres in AML blasts are typically shorter than expected for normal leukocytes, most AML cells do not show evidence of having gone through a “telomere crisis.” In chronic myeloid leukemia (CML), the difference between the telomere length in nonmalignant T cells and malignant blasts from the same patient was found to correlate with the remaining duration of the chronic phase. This observation supports that a mitotic clock is ticking in CML stem cells and that disease progression in CML heralds the onset of a “telomere crisis.” The presence of very short telomeres in tumor cells was found to predict disease progression in chronic lymphocytic leukemia, myeloma, and various solid tumors. In view of these findings longitudinal studies of telomere length in AML appear worthwhile.

Published
2017
Full Text
View/download PDF

28. Detection of G-quadruplex DNA in mammalian cells

Author

Henderson, A., primary, Wu, Y., additional, Huang, Y. C., additional, Chavez, E. A., additional, Platt, J., additional, Johnson, F. B., additional, Brosh, R. M., additional, Sen, D., additional, and Lansdorp, P. M., additional

Published
2013
Full Text
View/download PDF

29. Telomerase-Associated Protein TEP1 Is Not Essential for Telomerase Activity or Telomere Length Maintenance In Vivo

Author

Itie, A., Kickhoefer, V. A., Lansdorp, P. M., Hande, M. P., Snow, B. E., Liu, Y., Baerlocher, G., Robinson, M. O., Harrington, L., Yeung, D., Wakeham, A., and Siderovski, D. P.

Abstract

TEP1 is a mammalian telomerase-associated protein with similarity to the Tetrahymena telomerase protein p80. Like p80, TEP1 is associated with telomerase activity and the telomerase reverse transcriptase, and it specifically interacts with the telomerase RNA. To determine the role of mTep1 in telomerase function in vivo, we generated mouse embryonic stem (ES) cells and mice lacking mTep1. The mTep1-deficient (mTep1−/−) mice were viable and were bred for seven successive generations with no obvious phenotypic abnormalities. All murine tissues from mTep1−/− mice possessed a level of telomerase activity comparable to that in wild-type mice. In addition, analysis of several tissues that normally lack telomerase activity revealed no reactivation of telomerase activity in mTep1−/− mice. Telomere length, even in later generations of mTep1−/− mice, was equivalent to that in wild-type animals. ES cells deficient in mTep1 also showed no detectable alteration in telomerase activity or telomere length with increased passage in culture. Thus, mTep1 appears to be completely dispensable for telomerase function in vivo. Recently, TEP1 has been identified within a second ribonucleoprotein (RNP) complex, the vault particle. TEP1 can also specifically bind to a small RNA, vRNA, which is associated with the vault particle and is unrelated in sequence to mammalian telomerase RNA. These results reveal that TEP1 is an RNA binding protein that is not restricted to the telomerase complex and that TEP1 plays a redundant role in the assembly or localization of the telomerase RNP in vivo.

Published
2000
Full Text
View/download PDF

30. p53 Prohibits Propagation of Chromosome Segregation Errors that Produce Structural Aneuploidies

Author

Soto, Mar, Raaijmakers, Jonne A., Bakker, Bjorn, Spierings, Diana C.J., Lansdorp, Peter M., Foijer, Floris, and Medema, René H.

Abstract

The presence of an abnormal karyotype has been shown to be profoundly detrimental at the cellular and organismal levels but is an overt hallmark of cancer. Aneuploidy can lead to p53 activation and thereby prevents proliferation, but the exact trigger for p53 activation has remained controversial. Here, we have used a system to induce aneuploidy in untransformed human cells to explore how cells deal with different segregation errors. We show that p53 is activated only in a subset of the cells with altered chromosome content. Importantly, we find that at least a subset of whole-chromosome aneuploidies can be propagated in p53-proficient cells, indicating that aneuploidy does not always lead to activation of p53. Finally, we demonstrate that propagation of structural aneuploidies (gain or loss of part of a chromosome) induced by segregation errors is limited to p53-deficient cells.

Published
2017
Full Text
View/download PDF

35. Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma

Author

Foijer, Floris, Albacker, Lee A, Bakker, Bjorn, Spierings, Diana C, Yue, Ying, Xie, Stephanie Z, Davis, Stephanie, Lutum-Jehle, Annegret, Takemoto, Darin, Hare, Brian, Furey, Brinley, Bronson, Roderick T, Lansdorp, Peter M, Bradley, Allan, and Sorger, Peter K

Subjects
chromosomal instability, aneuploidy, spindle checkpoint, karyotype heterogeneity, Mad2, Human, Mouse
Abstract

Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases. The resulting DNA copy number variation and patterns of chromosome loss and gain are tumor-type specific, suggesting differential selective pressures on the two tumor cell types. DOI: http://dx.doi.org/10.7554/eLife.20873.001

Published
2017
Full Text
View/download PDF

36. Flow Cytometry and Immunoselection of Human Stem Cells.

Author

Walker, John M., Klug, Christopher A., Jordan, Craig T., Thomas, Terry E., Abraham, Sara J., and Lansdorp, Peter M.

Abstract

Human hematopoietic stem cells (HSCs) can be obtained from a variety of hematopoietic tissues, including bone marrow, blood, cord blood, and fetal liver. Various techniques have been used to fractionate hematopoietic cell populations based on differences in size and density, expression of cell-surface antigens, differential dye uptake, and sensitivity to cytotoxic drugs. The very low frequency of HSCs in hematopoietic tissues presents an enormous challenge to purification strategies aimed at isolation of sufficient cells of suitablpurity for further study. The most effective approaches invariably involve several cell-separation steps which differ in capacity and degree of selectivity. [ABSTRACT FROM AUTHOR]

Published
2002
Full Text
View/download PDF

37. Extensive Nuclear Reprogramming Underlies Lineage Conversion into Functional Trophoblast Stem-like Cells

Author

Benchetrit, Hana, Herman, Shay, van Wietmarschen, Niek, Wu, Tao, Makedonski, Kirill, Maoz, Noam, Yom Tov, Nataly, Stave, Danielle, Lasry, Rachel, Zayat, Valery, Xiao, Andrew, Lansdorp, Peter M., Sebban, Shulamit, and Buganim, Yosef

Abstract

Induced pluripotent stem cells (iPSCs) undergo extensive nuclear reprogramming and are generally indistinguishable from embryonic stem cells (ESCs) in their functional capacity and transcriptome and DNA methylation profiles. However, direct conversion of cells from one lineage to another often yields incompletely reprogrammed, functionally compromised cells, raising the question of whether pluripotency is required to achieve a high degree of nuclear reprogramming. Here, we show that transient expression of Gata3, Eomes, and Tfap2c in mouse fibroblasts induces stable, transgene-independent trophoblast stem-like cells (iTSCs). iTSCs possess transcriptional profiles highly similar to blastocyst-derived TSCs, with comparable methylation and H3K27ac patterns and genome-wide H2A.X deposition. iTSCs generate trophoectodermal lineages upon differentiation, form hemorrhagic lesions, and contribute to developing placentas in chimera assays, indicating a high degree of nuclear reprogramming, with no evidence of passage through a transient pluripotent state. Together, these data demonstrate that extensive nuclear reprogramming can be achieved independently of pluripotency.

Published
2015
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results