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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 2056-2064
Isolation of a Highly Quiescent Subpopulation of Primitive Leukemic
Cells in Chronic Myeloid Leukemia
Tessa Holyoake,
Xiaoyan Jiang,
Connie Eaves, and
Allen Eaves
From the Terry Fox Laboratory, BC Cancer Agency, Vancouver, British
Columbia, Canada.
Chronic myeloid leukemia (CML) is characterized by an increased
proliferative activity of the leukemic progenitors that produce an
elevated number of mature granulocytes. Nevertheless, cell cycle-active
agents, even in very high doses, are alone unable to eradicate the
leukemic clone, suggesting the presence of a rare subset of quiescent
leukemic stem cells. To isolate such cells, we first used Hoechst 33342 and Pyronin Y staining to obtain viable G0 and
G1/S/G2/M fractions of CD34+
cells by fluorescence-activated cell sorting (FACS) from 6 chronic-phase CML patients' samples and confirmed the quiescent and
cycling status of the 2 fractions by demonstration of expected patterns of Ki-67 and D cyclin expression. Leukemic
(Ph+/BCR-ABL+) cells with in vitro
progenitor activity and capable of engrafting immunodeficient mice were
identified in the directly isolated G0 cells. Single-cell
reverse transcriptase-polymerase chain reaction (RT-PCR)
analysis showed that many leukemic CD34+ G0
cells also expressed BCR-ABL mRNA. CD34+ from 8 CML
patients were also labeled with carboxyfluorescein diacetate
succinimidyl diester (CFSE) before being cultured (with and without
added growth factors) to allow viable cells that had remained quiescent
(ie, CFSE+) after 4 days to be retrieved by FACS.
Leukemic progenitors were again detected in all quiescent populations
isolated by this second strategy, including those exposed to a
combination of flt3-ligand, Steel factor, interleukin-3, interleukin-6,
and granulocyte colony-stimulating factor. These findings provide the
first direct and definitive evidence of a deeply but reversibly
quiescent subpopulation of leukemic cells in patients with CML with
both in vitro and in vivo stem cell properties.
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
B.-C. Lee, T. Cheng, G. B. Adams, E. C. Attar, N. Miura, S. B. Lee, Y. Saito, I. Olszak, D. Dombkowski, D. P. Olson, et al.
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|
|
|
|
|
|
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May 15, 2003;
101(10):
4088 - 4097.
[Abstract]
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|
|
|
|
|
|
|
Y. Guan, B. Gerhard, and D. E. Hogge
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101(8):
3142 - 3149.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Fukuda, R. G. Foster, S. B. Porter, and L. M. Pelus
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September 18, 2002;
100(7):
2463 - 2471.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Glimm, P. Tang, I. Clark-Lewis, C. von Kalle, and C. Eaves
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May 1, 2002;
99(9):
3454 - 3457.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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February 1, 2002;
4(1):
1 - 10.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. G. Jorgensen, M. A. Elliott, E. K. Allan, C. E. Carr, T. L. Holyoake, and K. D. Smith
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January 15, 2002;
99(2):
713 - 715.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Graham, H. G. Jorgensen, E. Allan, C. Pearson, M. J. Alcorn, L. Richmond, and T. L. Holyoake
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January 1, 2002;
99(1):
319 - 325.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. J. Weston, C. M. McConville, J. R. Mann, P. J. Darbyshire, S. Lawson, J. Gordon, P. A. H. Moss, A. Malcolm, R. Taylor, and T. Stankovic
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December 1, 2001;
61(23):
8547 - 8553.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Guzman, S. J. Neering, D. Upchurch, B. Grimes, D. S. Howard, D. A. Rizzieri, S. M. Luger, and C. T. Jordan
Nuclear factor-{kappa}B is constitutively activated in primitive human acute myelogenous leukemia cells
Blood,
October 15, 2001;
98(8):
2301 - 2307.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Fukuda and L. M. Pelus
Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34+ cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis
Blood,
October 1, 2001;
98(7):
2091 - 2100.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. P. Dialynas, M.-J. Lee, D. P. Gold, L.-e. Shao, A. L. Yu, M. J. Borowitz, and J. Yu
Preconditioning with fetal cord blood facilitates engraftment of primary childhood T-cell acute lymphoblastic leukemia in immunodeficient mice
Blood,
May 15, 2001;
97(10):
3218 - 3225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Thornley, D. R. Sutherland, R. Nayar, L. Sung, M. H. Freedman, and H. A. Messner
Replicative stress after allogeneic bone marrow transplantation: changes in cycling of CD34+CD90+ and CD34+CD90{-} hematopoietic progenitors
Blood,
March 15, 2001;
97(6):
1876 - 1878.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Li, S. Gillessen, M. H. Tomasson, G. Dranoff, D. G. Gilliland, and R. A. Van Etten
Interleukin 3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL
Blood,
March 1, 2001;
97(5):
1442 - 1450.
[Abstract]
[Full Text]
[PDF]
|
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|
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|
|
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T. L. Holyoake, X. Jiang, H. G. Jorgensen, S. Graham, M. J. Alcorn, C. Laird, A. C. Eaves, and C. J. Eaves
Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3
Blood,
February 1, 2001;
97(3):
720 - 728.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Bennaceur-Griscelli, C. Pondarre, V. Schiavon, W. Vainchenker, and L. Coulombel
Stromal cells retard the differentiation of CD34+CD38low/neg human primitive progenitors exposed to cytokines independent of their mitotic history
Blood,
January 15, 2001;
97(2):
435 - 441.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I.-H. Oh, A. Lau, and C. J. Eaves
During ontogeny primitive (CD34+CD38-) hematopoietic cells show altered expression of a subset of genes associated with early cytokine and differentiation responses of their adult counterparts
Blood,
December 15, 2000;
96(13):
4160 - 4168.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Glimm, I.-H. Oh, and C. J. Eaves
Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G2/M transit and do not reenter G0
Blood,
December 15, 2000;
96(13):
4185 - 4193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Hennemann, I.-H. Oh, J. Y. Chuo, C. P. Kalberer, P. D. Schley, S. Rose-John, R. K. Humphries, and C. J. Eaves
Efficient retrovirus-mediated gene transfer to transplantable human bone marrow cells in the absence of fibronectin
Blood,
October 1, 2000;
96(7):
2432 - 2439.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. H. Brummendorf, T. L. Holyoake, N. Rufer, M. J. Barnett, M. Schulzer, C. J. Eaves, A. C. Eaves, and P. M. Lansdorp
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Blood,
March 15, 2000;
95(6):
1883 - 1890.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Cheng, N. Rodrigues, H. Shen, Y. Yang, D. Dombkowski, M. Sykes, and D. T. Scadden
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Science,
March 10, 2000;
287(5459):
1804 - 1808.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
X. Jiang, A. Lopez, T. Holyoake, A. Eaves, and C. Eaves
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96(22):
12804 - 12809.
[Abstract]
[Full Text]
[PDF]
|
|
|
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