Terry Fox Laboratory | Dr. Peter Lansdorp

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About

Dr. Peter M. Lansdorp, MD, PhD
Senior Scientist

• Professor, Medicine, University of British Columbia (UBC)
• Associate Member, Medical Genetics, UBC
• Associate Member, Experimental Medicine, UBC
• Associate Member, Pathology & Laboratory Medicine, UBC

Education:
MD, Erasmus University Rotterdam, 1976
PhD, Experimental Hematology, University of Amsterdam, 1985

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Research Interest

Asymmetric cell divisions and stem cell biology
Genetic instability, aging and cancer
Replication and repair of G-rich DNA and telomere repeats
Fluorescence in situ hybridization and flow cytometry

Asymmetric cell divisions are required for the development of all multi-cellular organisms. Many mechanisms are known to help secure differences between daughter cells following a parental cell division. We are interested in exploring the possibility that differences in parental cells before they divide contribute to differences between daughter cells as well. For example, it seems possible that chromatin differences between sister chromatids co-regulate the expression of specific genes as predicted by the “silent sister hypothesis” (1). In order to test this hypothesis it is necessary to reliably distinguish between sister chromatids. We recently described a novel approach to identify and study sister chromatids (2). Current studies focus on testing the “silent sister hypothesis” using cells that divide asymmetrically and cells in which asymmetry is not obvious such as self-renewing normal and malignant (stem) cells.

Accurate replication of DNA and faithful segregation of chromosomes are essential for all forms of life. In multi-cellular organisms, the control of these processes differs markedly between various cell types and between organisms (3). For example, the number of cell divisions is tightly controlled in adult blood-forming stem cells, whereas embryonic stem cells are essentially immortal. Furthermore, most adult stem cells are typically quiescent, whereas embryonic stem cells turnover rapidly. The number of cell divisions that adult stem cells can undergo seems much more tightly controlled in humans than in mice, perhaps because tumor growth poses a greater risk to reproductive fitness in humans (with a longer lifespan and a larger body mass) than in mice (3). We previously engineered murine ES cells (4) with specific defects in the replication of chromosome ends (telomeres). Surprisingly, such cells appear to grow normally until differentiation is induced. In order to study the molecular mechanisms that underpin these observations, we are using these and other ES cells expressing fluorescent reporter constructs before and after various genetic manipulations. The goal of these studies is to characterize the pathways involved in cell cycle checkpoints, telomere maintenance and DNA damage responses in ES cells before and after induction of differentiation.

In all vertebrates telomeres are characterized by TTAGGG repeats and associated proteins. A minimum number of telomere repeats is needed at each end in order to distinguish a normal end form a double strand break and protect chromosome ends from fusion and degradation. Critically short or truncated telomeres trigger a DNA damage response that can cause cell cycle arrest or cell death. Telomeric DNA is lost with each round of cell division via several distinct pathways (5). Lost telomere repeats are normally replenished by the enzyme telomerase, a reverse transcriptase which can add telomere repeats to the 3’ end of chromosomes using an RNA template. Telomerase levels appear to be limiting in normal human blood forming stem cells (6). We have developed novel tools to measure the telomere length in individual cells and individual chromosomes (7, 8) and these quantitative fluorescence in situ hybridization techniques are used to address questions about the role of telomeres in normal aging, tumor progression and specific genetic, hematological and immune disorders. Based on our studies in C.elegans (9) we are partcilarly interested in guanine-rich DNA capable of forming higher order structures known guanine quadruplex (G4) DNA. We have developed a panel of monoclonal antibodies against different G4 DNA structures to study on the role of G4 DNA in the regulation of gene expression and telomere biology.

Lansdorp PM. Immortal strands? Give me a break. Cell 129: 1244-1247, 2007.
Falconer E, Chavez EA, Henderson A, Poon SSS, McKinney S, Brown L, Huntsman DG & Lansdorp PM. Identification of sister chromatids by DNA template strand sequences. Nature (Epub ahead of print on Dec 16, 2009).
Lansdorp PM. Telomeres and disease. EMBO J 28: 2532-2540, 2009
Ding, H, Schertzer M, Wu X, Gersteinsen M, Selig S, Kammori M, Pourvali R, Poon S, Vulto I, Chavez E, Tam PPL, Nagy A & Lansdorp PM. Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein. Cell 117, 873-86 (2004).
Lansdorp PM. Major Cutbacks at chromosome ends. Trends Biochem Sci 30:388-395, 2005.
Aubert G & Lansdorp P. Telomeres and aging. Physiol Rev 82:557-579, 2008.
Lansdorp, P. M. et al. Heterogeneity in telomere length of human chromosomes. Hum Mol Genet 5, 685-91 (1996).
Baerlocher, G. M., Vulto, I., de Jong, G. & Lansdorp, P. M. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protoc 1, 2365-76 (2006).
Cheung, I., Schertzer, M., Rose, A. & Lansdorp, P. M. Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA. Nat Genet 31, 405-9 (2002).

Publications

Falconer E, Chavez EA, Henderson A, Poon SSS, McKinney S, Brown L, Huntsman DG & Lansdorp PM. Identification of sister chromatids by DNA template strand sequences. Nature 463:93-7, 2010
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Calado RT, Regal JA, Kleiner DE, Schrump DS, Peterson NR, Pons V, Chanock SJ, Lansdorp PM, & Young NS. A spectrum of severe familial liver disorders associate with telomerase mutations. PLoS One 4 (11): e7926, 2009.
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Hills M, & Lansdorp PM. Short telomeres resulting from heritable mutations in the telomerase reverse transcriptase gene predispose for a variety of malignancies. Ann N Y Acad Sci 1176: 178-90, 2009.
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Breakey VR, Meyn S, Ng V, Allen C, Dokal I, Lansdorp PM, Abla O, & Dror Y. Hepatitis-associated aplastic anemia presenting as a familial bone marrow failure syndrome. J Pediatr Hematol Oncol 31 (11): 884-7, 2009.
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Lansdorp PM. Telomeres and disease. EMBO J 28 (17): 2532-40 2009.
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Banath JP, Banuelos CA, Klokov D, MacPhail SM, Lansdorp PM, & Olive PL. Explanation for excessive DNA single-strand breaks and endogenous repair foci in pluripotent mouse embryonic stem cells. Exp Cell Res 315 (8): 1505-20, 2009.
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Calado RT, Regal JA, Hills M, Yewdell WT, Dalmazzo LF, Zago MA, Lansdorp PM, Hogge D, Chanock SJ, Estey EH, Falcao RP, & Young NS. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc Natl Acad Sci U S A 106 (4): 1187-92, 2009.
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Decker ML, Chavez E, Vulto I, & Lansdorp PM. Telomere length in Hutchinson-Gilford progeria syndrome. Mech Ageing Dev 130 (6): 377-83, 2009.
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Gourronc FA, Robertson MM, Herrig AK, Lansdorp PM, Goldman FD, & Klingelhutz AJ. Proliferative defects in dyskeratosis congenita skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA component, TERC. Exp Dermatol, 2009. (Epub ahead of print)
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Hills M, Lucke K, Chavez EA, Eaves CJ, & Lansdorp PM. Probing the mitotic history and developmental stage of hematopoietic cells using single telomere length analysis (STELA). Blood 113 (23): 5765-75, 2009.
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Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, Vulto I, Xie M, Qi X, Tuder RM, Phillips JA, 3^rd, Lansdorp PM, Loyd JE, & Armanios MY. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A 105 (35): 13051-6, 2008.
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Aubert G, & Lansdorp PM. Telomeres and aging. Physiol Rev 88 (2): 557-79, 2008.
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Banuelos CA, Banath JP, MacPhail SH, Zhao J, Eaves CA, O’Connor MD, Lansdorp PM, & Olive PL. Mouse but not human embryonic stem cells are deficient in rejoining of ionizing radiation-induced DNA double-strand breaks. DNA Repair (Amst) 7 (9): 1471-83, 2008.
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Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, & Riddell SR. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 118 (1): 294-305, 2008.
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Goldman FD, Aubert G, Klingelhutz AJ, Hills M, Cooper SR, Hamilton WS, Schlueter AJ, Lambie K, Eaves CJ, & Lansdorp PM. Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita. Blood 111 (9): 4523-31, 2008.
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Halaschek-Wiener J, Vulto I, Fornika D, Collins J, Connors JM, Le ND, Lansdorp PM, & Brooks-Wilson A. Reduced telomere length variation in healthy oldest old. Mech Ageing Dev 129 (11): 638-41, 2008.
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Liu Y, Bohr VA & Lansdorp P. Telomere, telomerase and aging. Mech Ageing Dev 129: 1-2, 2008.
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Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C & Riddell SR. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 118: 294-305, 2008.
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Goldman FD, Aubert G, Klingelhutz AJ, Hills M, Cooper SR, Hamilton WS, Schlueter A, Lambie K, Eaves CJ & Lansdorp PM. Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita. Blood 2008. (Epub ahead of print).
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Lansdorp PM. Telomeres, stem cells and hematology. Blood 111: 1759-1766, 2008.
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Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM & Alter BP. TINF2, a component of the Shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 82(2): 501-9, 2008.
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Alter BP, Baerlocher GM, Savage SA, Chanock SJ, Weksler BB, Willner JP, Peters JA, Giri N, & Lansdorp PM. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood 110 (5): 1439-47, 2007.
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Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA, 3^rd, Lansdorp PM, Greider CW, & Loyd JE. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 356 (13): 1317-26, 2007.
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Baerlocher GM, Rice K, Vulto I, & Lansdorp PM. Longitudinal data on telomere length in leukocytes from newborn baboons support a marked drop in stem cell turnover around 1 year of age. Aging Cell 6 (1): 121-3, 2007.
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Lansdorp PM. Immortal strands? Give me a break. Cell 129 (7): 1244-7, 2007.
View Abstract

Baerlocher GM, Vulto I, de Jong G, & Lansdorp PM. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protoc 1 (5): 2365-76, 2006.
View Abstract

Cheung I, Schertzer M, Rose A, & Lansdorp PM. High incidence of rapid telomere loss in telomerase-deficient Caenorhabditis elegans. Nucleic Acids Res 34 (1): 96-103, 2006.
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Lansdorp PM. Stress, social rank and leukocyte telomere length. Aging Cell 5 (6): 583-4, 2006.
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Lansdorp PM. Major cutbacks at chromosome ends. Trends Biochem Sci 30 (7): 388-95, 2005.
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Ly H, Schertzer M, Jastaniah W, Davis J, Yong SL, Ouyang Q, Blackburn EH, Parslow TG, & Lansdorp PM. Identification and functional characterization of 2 variant alleles of the telomerase RNA template gene (TERC) in a patient with dyskeratosis congenita. Blood 106 (4): 1246-52, 2005.
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Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, & Young NS. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 352 (14): 1413-24, 2005.
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Cheung I, Schertzer M, Baross A, Rose AM, Lansdorp PM, & Baird DM. Strain-specific telomere length revealed by single telomere length analysis in Caenorhabditis elegans. Nucleic Acids Res 32 (11): 3383-91, 2004.
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Ding H, Schertzer M, Wu X, Gertsenstein M, Selig S, Kammori M, Pourvali R, Poon S, Vulto I, Chavez E, Tam PP, Nagy A, & Lansdorp PM. Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein. Cell 117 (7): 873-86, 2004.
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Baerlocher GM, Mak J, Roth A, Rice KS, & Lansdorp PM. Telomere shortening in leukocyte subpopulations from baboons. J Leukoc Biol 73 (2): 289-96, 2003.
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Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS, Read EJ, Lansdorp PM, & Young NS. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 362 (9396): 1628-30, 2003.
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Roth A, Vercauteren S, Sutherland HJ, & Lansdorp PM. Telomerase is limiting the growth of acute myeloid leukemia cells. Leukemia 17 (12): 2410-7, 2003.
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Roth A, Yssel H, Pene J, Chavez EA, Schertzer M, Lansdorp PM, Spits H, & Luiten RM. Telomerase levels control the lifespan of human T lymphocytes. Blood 102 (3): 849-57, 2003.
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Tchirkov A, & Lansdorp PM. Role of oxidative stress in telomere shortening in cultured fibroblasts from normal individuals and patients with ataxia-telangiectasia. Hum Mol Genet 12 (3): 227-32, 2003.
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Van Ziffle JA, Baerlocher GM, & Lansdorp PM. Telomere length in subpopulations of human hematopoietic cells. Stem Cells 21 (6): 654-60, 2003.
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Yamaguchi H, Baerlocher GM, Lansdorp PM, Chanock SJ, Nunez O, Sloand E, & Young NS. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood 102 (3): 916-8, 2003.
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Cheung I, Schertzer M, Rose A, & Lansdorp PM. Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA. Nat Genet 31 (4): 405-9, 2002.
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Verfaillie CM, Pera MF, & Lansdorp PM. Stem cells: hype and reality. Hematology Am Soc Hematol Educ Program: 369-91, 2002.
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Brummendorf TH, Maciejewski JP, Mak J, Young NS, & Lansdorp PM. Telomere length in leukocyte subpopulations of patients with aplastic anemia. Blood 97 (4): 895-900, 2001.
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Hande MP, Balajee AS, Tchirkov A, Wynshaw-Boris A, & Lansdorp PM. Extra-chromosomal telomeric DNA in cells from Atm(-/-) mice and patients with ataxia-telangiectasia. Hum Mol Genet 10 (5): 519-28, 2001.
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Poon SS, & Lansdorp PM. Measurements of telomere length on individual chromosomes by image cytometry. Methods Cell Biol 64: 69-96, 2001.
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Rufer N, Brummendorf TH, Chapuis B, Helg C, Lansdorp PM, & Roosnek E. Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation. Blood 97 (2): 575-7, 2001.
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Brummendorf TH, Holyoake TL, Rufer N, Barnett MJ, Schulzer M, Eaves CJ, Eaves AC, & Lansdorp PM. Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. Blood 95 (6): 1883-90, 2000.
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Lansdorp PM. Repair of telomeric DNA prior to replicative senescence. Mech Ageing Dev 118 (1-2): 23-34, 2000.
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Lanza RP, Cibelli JB, Blackwell C, Cristofalo VJ, Francis MK, Baerlocher GM, Mak J, Schertzer M, Chavez EA, Sawyer N, Lansdorp PM, & West MD. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 288 (5466): 665-9, 2000.
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Liu Y, Snow BE, Hande MP, Baerlocher G, Kickhoefer VA, Yeung D, Wakeham A, Itie A, Siderovski DP, Lansdorp PM, Robinson MO, & Harrington L. Telomerase-associated protein TEP1 is not essential for telomerase activity or telomere length maintenance in vivo. Mol Cell Biol 20 (21): 8178-84, 2000.
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Martens UM, Chavez EA, Poon SS, Schmoor C, & Lansdorp PM. Accumulation of short telomeres in human fibroblasts prior to replicative senescence. Exp Cell Res 256 (1): 291-9, 2000.
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d’Adda di Fagagna F, Hande MP, Tong WM, Lansdorp PM, Wang ZQ, & Jackson SP. Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability. Nat Genet 23 (1): 76-80, 1999.
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Hande MP, Samper E, Lansdorp P, & Blasco MA. Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J Cell Biol 144 (4): 589-601, 1999.
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Poon SS, Martens UM, Ward RK, & Lansdorp PM. Telomere length measurements using digital fluorescence microscopy. Cytometry 36 (4): 267-78, 1999.
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Rufer N, Brummendorf TH, Kolvraa S, Bischoff C, Christensen K, Wadsworth L, Schulzer M, & Lansdorp PM. Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med 190 (2): 157-67, 1999.
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Surralles J, Hande MP, Marcos R, & Lansdorp PM. Accelerated telomere shortening in the human inactive X chromosome. Am J Hum Genet 65 (6): 1617-22, 1999.
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Wan TS, Martens UM, Poon SS, Tsao SW, Chan LC, & Lansdorp PM. Absence or low number of telomere repeats at junctions of dicentric chromosomes. Genes Chromosomes Cancer 24 (1): 83-6, 1999.
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Brummendorf TH, Dragowska W, Zijlmans J, Thornbury G, & Lansdorp PM. Asymmetric cell divisions sustain long-term hematopoiesis from single-sorted human fetal liver cells. J Exp Med 188 (6): 1117-24, 1998.
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Martens UM, Zijlmans JM, Poon SS, Dragowska W, Yui J, Chavez EA, Ward RK, & Lansdorp PM. Short telomeres on human chromosome 17p. Nat Genet 18 (1): 76-80, 1998.
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Rufer N, Dragowska W, Thornbury G, Roosnek E, & Lansdorp PM. Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat Biotechnol 16 (8): 743-7, 1998.
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Yui J, Chiu CP, & Lansdorp PM. Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. Blood 91 (9): 3255-62, 1998.
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Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, & Greider CW. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91 (1): 25-34, 1997.
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Lansdorp PM. Self-renewal of stem cells. Biol Blood Marrow Transplant 3 (4): 171-8, 1997.
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Zijlmans JM, Martens UM, Poon SS, Raap AK, Tanke HJ, Ward RK, & Lansdorp PM. Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG3 repeats. Proc Natl Acad Sci U S A 94 (14): 7423-8, 1997.
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Chiu CP, Dragowska W, Kim NW, Vaziri H, Yui J, Thomas TE, Harley CB, & Lansdorp PM. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells 14 (2): 239-48, 1996.
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Lansdorp PM, Verwoerd NP, van de Rijke FM, Dragowska V, Little MT, Dirks RW, Raap AK, & Tanke HJ. Heterogeneity in telomere length of human chromosomes. Hum Mol Genet 5 (5): 685-91, 1996.
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Rebel VI, Miller CL, Eaves CJ, & Lansdorp PM. The repopulation potential of fetal liver hematopoietic stem cells in mice exceeds that of their liver adult bone marrow counterparts. Blood 87 (8): 3500-7, 1996.
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Sauvageau G, Thorsteinsdottir U, Eaves CJ, Lawrence HJ, Largman C, Lansdorp PM, & Humphries RK. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev 9 (14): 1753-65, 1995.
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Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, & Lansdorp PM. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci U S A 91 (21): 9857-60, 1994.
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Lansdorp PM, Dragowska W, & Mayani H. Ontogeny-related changes in proliferative potential of human hematopoietic cells. J Exp Med 178 (3): 787-91, 1993.
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Lansdorp PM, & Dragowska W. Long-term erythropoiesis from constant numbers of CD34+ cells in serum-free cultures initiated with highly purified progenitor cells from human bone marrow. J Exp Med 175 (6): 1501-9, 1992.
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Lansdorp PM, Sutherland HJ, & Eaves CJ. Selective expression of CD45 isoforms on functional subpopulations of CD34+ hemopoietic cells from human bone marrow. J Exp Med 172 (1): 363-6, 1990.
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Sutherland HJ, Eaves CJ, Eaves AC, Dragowska W, & Lansdorp PM. Characterization and partial purification of human marrow cells capable of initiating long-term hematopoiesis in vitro. Blood 74 (5): 1563-70, 1989.
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van den Engh G, Trask B, Lansdorp P, & Gray J. Improved resolution of flow cytometric measurements of Hoechst- and chromomycin-A3-stained human chromosomes after addition of citrate and sulfite. Cytometry 9 (3): 266-70, 1988.
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Lansdorp PM, Aalberse RC, Bos R, Schutter WG, & Van Bruggen EF. Cyclic tetramolecular complexes of monoclonal antibodies: a new type of cross-linking reagent. Eur J Immunol 16 (6): 679-83, 1986.
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