Lansdorp, Peter
Associate Member, Dept of Pathology and Laboratory Medicine
http://www.bccrc.ca/tfl/people_plansdor.html
Research Interests
The major focus of the research in my laboratory is on the role of genetic instability in aging and cancer. Ongoing studies are very diverse in nature, ranging from molecular studies on the role of helicases in the genomic stability of guanine-rich DNA (using C.elegans as a model) to studies of chromosome ends (telomeres) in the biology of normal and malignant cells. An area of specific interest is the role of telomeres and telomerase in stem cells and lymphocytes.
Telomeres are characterized in all vertebrates by TTAGGG repeats and associated proteins. Telomeres protect chromosome ends from fusion and degradation. The loss of telomere repeats appears to limit the proliferation of normal human somatic cells. Loss of telomere function results in apoptosis or replicative senescence or, in very rare instances, in genetic instability that accelerates malignant progression. We have developed novel tools to measure the telomere length in individual cells and individual chromosomes. 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.
The interest in telomere biology originates from our previous work with purified blood-forming stem cells. For these studies we developed techniques to purify stem cells based on monoclonal antibodies, multiparameter fluorescence activated cell sorting techniques and magnetic cell separation techniques (for information on large scale cell separation techniques based on technolog). We showed that purified human and murine stem and progenitor cells from tissues at different stages of development display marked differences in functional properties. Subsequently, we found that, in humans, such functional differences coincide with measurable changes in telomere length. These observations support the idea that the number of times normal human (stem) cells can divide is restricted by the number of telomeric repeats on specific chromosomes. Recently, we obtained a grant from the Canada Foundation for Innovation to set up a Stem Cell Centre in Vancouver. This grant will allow us to build several new cell sorters and related infrastructure (in collaboration with Dr. Ger van den Engh in Seattle) in the new BC Cancer Research Centre (under construction now with completion expected at the end of 2004).
Current studies focus on the molecular mechanisms of telomere attrition in relation to DNA replication and repair in normal and malignant cells. Such studies include manipulation of known and novel pathways involved in telomere biology and function using lentiviral mediated gene transfer into lymphocytes and various stem cells.
Selected Publications:
Baerlocher GM, Lansdorp PM. Telomere length measurements in leukocyte subsets by automated multicolor flow-FISH. Cytometry 55A(1):1-6. (2003).
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).
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).
Roth A, Vercauteren S, Sutherland HJ, Lansdorp PM. Telomerase is limiting the growth of acute myeloid leukemia cells. Leukemia . (2003).
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).
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).
Van Ziffle JA, Baerlocher GM, Lansdorp PM. Telomere length in subpopulations of human hematopoietic cells. Stem Cells 21(6):654-60. (2003).
[View Abstract - PubMed 14595125] Request Paper
Awaya N, Baerlocher GM, Manley TJ, Sanders JE, Mielcarek M, Torok-Storb B, Lansdorp PM. Telomere shortening in hematopoietic stem cell transplantation: a potential mechanism for late graft failure? Biol Blood Marrow Transplant 8(11):597-600. (2002).
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).
[View Abstract - PubMed 12101400] Request Paper
Verfaillie CM, Pera MF, Lansdorp PM. Stem cells: hype and reality. Hematology (Am Soc Hematol Educ Program) :369-91. (2002).
Rufer N, Migliaccio M, Antonchuk J, Humphries RK, Roosnek E, Lansdorp PM. Transfer of the human telomerase reverse transcriptase (TERT) gene into T lymphocytes results in extension of replicative potential. Blood 98(3):597-603. (2001).
d'Adda di Fagagna F, Hande MP, Tong WM, Roth D, Lansdorp PM, Wang ZQ, Jackson SP. Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr Biol 11(15):1192-6. (2001).
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).