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Telomerase Regulation, Cell Cycle, and Telomere Stability in Primitive Hematopoietic Cells
Monika Engelhardt,
Rakesh Kumar,
Juan Albanell,
Ruth Pettengell,
Wei Han, and
Malcolm A.S. Moore
From the Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York, NY; and Laboratory of Cell Growth Regulation, U.T. M.D. Anderson Cancer Center, Houston, TX.
Low levels of telomerase activity have recently been detected in human primitive hematopoietic cells, however, blood cells exhibit telomere shortening on cell proliferation. This challenging observation led us to study telomerase regulation and telomere length in human hematopoietic progenitor cells from fetal liver (FL), cord blood (CB), peripheral blood (PB), and bone marrow (BM). We found telomerase activity in CD34+/CD38+ cells exceeding levels in CD34+/CD38-, CD34-, and mononuclear cells (P < .05). Baseline telomerase activity was highest in BM (n = 5) CD34+ cells, followed by PB (n = 20), CB (n = 11), and FL (n = 1). Within 48 hours to 72 hours of in vitro culture of CD34+ cells in the presence of cytokines (KL, interleukin-3 [IL-3], IL-6, erythropoietin, granulocyte colony-stimulating factor), telomerase activity was upregulated, peaked after 1 week of culture, and decreased to baseline levels or below detection after 3 to 4 weeks. Stimulation of CD34+ cells with single cytokines resulted in no or minor telomerase upregulation, whereas cytokine combinations resulted in a significant telomerase increase (P < .001). There was a correlation between telomerase activity, cell cycle status by BrdU incorporation, and induction of phosphorylated retinoblastoma protein, CDC2, CDK2, cyclin D1, and cyclin A, but not cyclin E and B1 after 72 hours with multiple (but not single) cytokines. In nonexpanding CD34+ cells, telomerase was low or undetectable. Secondary CD34+ cells showed a reduced ability to upregulate telomerase activity. Antiproliferative cytokines such as transforming growth factor- 1 and high concentrations of all-trans-retinoic acid in cytokine-supported CD34+ cultures downmodulated telomerase activity. Average telomere lengths were 10.4 kbp, 7.4 kbp, and 7.6 kbp in CB, PB, and BM CD34+ cells, respectively. In ex vivo expansion cultures, an average telomeric DNA loss of 1 to 2 kbp over 4 weeks was observed. However, the rate of base pair loss per population doubling was significantly lower during the first 2 weeks, when telomerase was upregulated, than during weeks 3 and 4 of culture. In summary, telomerase is upregulated in response to cytokine-induced proliferation and cell cycle activation in primitive hematopoietic cells. Telomerase is downregulated between weeks 3 and 4 of ex vivo expansion culture linked with decreased proliferation and greater expansion of more mature cell subsets. Our data suggest that telomerase activity in hematopoietic cells reduces, but does not prevent, telomere shortening on proliferation.
Blood, Vol. 90 No. 1 (July 1), 1997:
pp. 182-193
© 1997 by The American Society of Hematology.
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108(3):
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[Abstract]
[Full Text]
[PDF]
|
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|
|
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|
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O. Beyne-Rauzy, N. Prade-Houdellier, C. Demur, C. Recher, J. Ayel, G. Laurent, and V. Mansat-De Mas
Tumor necrosis factor-{alpha} inhibits hTERT gene expression in human myeloid normal and leukemic cells
Blood,
November 1, 2005;
106(9):
3200 - 3205.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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J. C. Y. Wang, J. K. Warner, N. Erdmann, P. M. Lansdorp, L. Harrington, and J. E. Dick
Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells
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October 4, 2005;
102(40):
14398 - 14403.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Kindler
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J. Leukoc. Biol.,
October 1, 2005;
78(4):
836 - 844.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Armstrong, G. Saretzki, H. Peters, I. Wappler, J. Evans, N. Hole, T. von Zglinicki, and M. Lako
Overexpression of Telomerase Confers Growth Advantage, Stress Resistance, and Enhanced Differentiation of ESCs Toward the Hematopoietic Lineage
Stem Cells,
April 1, 2005;
23(4):
516 - 529.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Zimmermann, S. Glaser, R. Ketteler, C. F. Waller, U. Klingmuller, and U. M. Martens
Effects of Telomerase Modulation in Human Hematopoietic Progenitor Cells
Stem Cells,
September 1, 2004;
22(5):
741 - 749.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Gammaitoni, K. C. Weisel, M. Gunetti, K.-D. Wu, S. Bruno, S. Pinelli, A. Bonati, M. Aglietta, M. A. S. Moore, and W. Piacibello
Elevated telomerase activity and minimal telomere loss in cord blood long-term cultures with extensive stem cell replication
Blood,
June 15, 2004;
103(12):
4440 - 4448.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A.G. Van Ziffle, G. M. Baerlocher, and P. M. Lansdorp
Telomere Length in Subpopulations of Human Hematopoietic Cells
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November 1, 2003;
21(6):
654 - 660.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Shammas, R. J. Shmookler Reis, M. Akiyama, H. Koley, D. Chauhan, T. Hideshima, R. K. Goyal, L. H. Hurley, K. C. Anderson, and N. C. Munshi
Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma
Mol. Cancer Ther.,
September 1, 2003;
2(9):
825 - 833.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-D. Wu, L. M. Orme, J. Shaughnessy Jr, J. Jacobson, B. Barlogie, and M. A. S. Moore
Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival
Blood,
June 15, 2003;
101(12):
4982 - 4989.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Inaba, T. Hiruma, A. Togayachi, H. Iwasaki, X.-H. Wang, Y. Furukawa, R. Sumi, T. Kudo, K. Fujimura, T. Iwai, et al.
A novel I-branching beta -1,6-N-acetylglucosaminyltransferase involved in human blood group I antigen expression
Blood,
April 1, 2003;
101(7):
2870 - 2876.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Fuller
Hematopoietic Stem Cells and Aging
Sci. Aging Knowl. Environ.,
June 26, 2002;
2002(25):
pe11 - 11.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
I. Thornley and M. H. Freedman
Telomeres, X-Inactivation Ratios, and Hematopoietic Stem Cell Transplantation in Humans: A Review
Stem Cells,
May 1, 2002;
20(3):
198 - 204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Samper, P. Fernandez, R. Eguia, L. Martin-Rivera, A. Bernad, M. A. Blasco, and M. Aracil
Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells
Blood,
April 15, 2002;
99(8):
2767 - 2775.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Boklan, G. Nanjangud, K. L. MacKenzie, C. May, M. Sadelain, and M. A. S. Moore
Limited Proliferation and Telomere Dysfunction following Telomerase Inhibition in Immortal Murine Fibroblasts
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April 1, 2002;
62(7):
2104 - 2114.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Thornley, R. Sutherland, R. Wynn, R. Nayar, L. Sung, G. Corpus, T. Kiss, J. Lipton, J. Doyle, F. Saunders, et al.
Early hematopoietic reconstitution after clinical stem cell transplantation: evidence for stochastic stem cell behavior and limited acceleration in telomere loss
Blood,
April 1, 2002;
99(7):
2387 - 2396.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N.-p. Weng
Interplay between telomere length and telomerase in human leukocyte differentiation and aging
J. Leukoc. Biol.,
December 1, 2001;
70(6):
861 - 867.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. Vonderheide, K. S. Anderson, W. C. Hahn, M. O. Butler, J. L. Schultze, and L. M. Nadler
Characterization of HLA-A3-restricted Cytotoxic T Lymphocytes Reactive against the Widely Expressed Tumor Antigen Telomerase
Clin. Cancer Res.,
November 1, 2001;
7(11):
3343 - 3348.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Wright, E. L. Jones, J. F. Mayer, S. Oehninger, W. E. Gibbons, and S. E. Lanzendorf
Characterization of telomerase activity in the human oocyte and preimplantation embryo
Mol. Hum. Reprod.,
October 1, 2001;
7(10):
947 - 955.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Stewart, S. Zhong, J.-F. Lambert, G. A. Colvin, M. Abedi, M. S. Dooner, C. I. McAuliffe, H. Wang, C. Hsieh, and P. J. Quesenberry
Host marrow stem cell potential and engraftability at varying times after low-dose whole-body irradiation
Blood,
August 15, 2001;
98(4):
1246 - 1251.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Catalano, M. Romano, I. Robuffo, L. Strizzi, and A. Procopio
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Am. J. Pathol.,
August 1, 2001;
159(2):
721 - 731.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Engelhardt, J. Finke, N. Rufer, T. H. Brummendorf, B. Chapuis, C. Helg, P. M. Lansdorp, and E. Roosnek
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Blood,
August 1, 2001;
98(3):
888 - 890.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Chaves-Dias, T. R. Hundley, A. M. Gilfillan, A. S. Kirshenbaum, J. R. Cunha-Melo, D. D. Metcalfe, and M. A. Beaven
Induction of Telomerase Activity During Development of Human Mast Cells from Peripheral Blood CD34+ Cells: Comparisons with Tumor Mast-Cell Lines
J. Immunol.,
June 1, 2001;
166(11):
6647 - 6656.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Yang, S. Kyo, M. Takatura, and L. Sun
Autocrine Transforming Growth Factor {beta} Suppresses Telomerase Activity and Transcription of Human Telomerase Reverse Transcriptase in Human Cancer Cells
Cell Growth Differ.,
February 1, 2001;
12(2):
119 - 127.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M.-S. Dai, C. R. Mantel, Z.-B. Xia, H. E. Broxmeyer, and L. Lu
An expansion phase precedes terminal erythroid differentiation of hematopoietic progenitor cells from cord blood in vitro and is associated with up-regulation of cyclin E and cyclin-dependent kinase 2
Blood,
December 1, 2000;
96(12):
3985 - 3987.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Migliaccio, M. Amacker, T. Just, P. Reichenbach, D. Valmori, J.-C. Cerottini, P. Romero, and M. Nabholz
Ectopic Human Telomerase Catalytic Subunit Expression Maintains Telomere Length But Is Not Sufficient for CD8+ T Lymphocyte Immortalization
J. Immunol.,
November 1, 2000;
165(9):
4978 - 4984.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Finnon, A. R.J. Silver, and S. D. Bouffler
Upregulation of telomerase activity by X-irradiation in mouse leukaemia cells is independent of Tert, Terc, Tnks and Myc transcription
Carcinogenesis,
April 1, 2000;
21(4):
573 - 578.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Cooney, W. G. Bradley, S. C. Symko, S. T. Patel, and P. K. Groncy
Hypertensive Encephalopathy: Complication in Children Treated for Myeloproliferative Disorders-Report of Three Cases
Radiology,
March 1, 2000;
214(3):
711 - 716.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Engelhardt, K. Mackenzie, P. Drullinsky, R. T. Silver, and M. A. S. Moore
Telomerase Activity and Telomere Length in Acute and Chronic Leukemia, Pre- and Post-ex Vivo Culture
Cancer Res.,
February 1, 2000;
60(3):
610 - 617.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
J. Albanell, G. J. Bosl, V. E. Reuter, M. Engelhardt, S. Franco, M. A. S. Moore, and E. Dmitrovsky
Telomerase Activity in Germ Cell Cancers and Mature Teratomas
J Natl Cancer Inst,
August 4, 1999;
91(15):
1321 - 1326.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Tamura, H. Liu, and H. Takahashi
Auxin Induction of Cell Cycle Regulated Activity of Tobacco Telomerase
J. Biol. Chem.,
July 23, 1999;
274(30):
20997 - 21002.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. de Haan and G. Van Zant
Dynamic Changes in Mouse Hematopoietic Stem Cell Numbers During Aging
Blood,
May 15, 1999;
93(10):
3294 - 3301.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Ohyashiki, H. Iwama, N. Yahata, K. Ando, S. Hayashi, J. W. Shay, and K. Ohyashiki
Telomere Stability Is Frequently Impaired in High-Risk Groups of Patients with Myelodysplastic Syndromes
Clin. Cancer Res.,
May 1, 1999;
5(5):
1155 - 1160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Fossel
Telomerase and the Aging Cell: Implications for Human Health
JAMA,
June 3, 1998;
279(21):
1732 - 1735.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Ball, F. M. Gibson, S. Rizzo, J. A. Tooze, J. C.W. Marsh, and E. C. Gordon-Smith
Progressive Telomere Shortening in Aplastic Anemia
Blood,
May 15, 1998;
91(10):
3582 - 3592.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Bodnar, M. Ouellette, M. Frolkis, S. E. Holt, C. Chiu, G. B. Morin, C. B. Harley, J. W. Shay, S. Lichtsteiner, and W. E. Wright
Extension of Life-Span by Introduction of Telomerase into Normal Human Cells
Science,
January 16, 1998;
279(5349):
349 - 352.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
R. Notaro, A. Cimmino, D. Tabarini, B. Rotoli, and L. Luzzatto
In vivo telomere dynamics of human hematopoietic stem cells
PNAS,
December 9, 1997;
94(25):
13782 - 13785.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
