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Prepublished online as a Blood First Edition Paper on December 5, 2002; DOI 10.1182/blood-2002-10-3062.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3142-3149
NEOPLASIA
Detection, isolation, and stimulation of quiescent primitive
leukemic progenitor cells from patients with acute myeloid leukemia
(AML)
Yinghui Guan,
Brigitte Gerhard, and
Donna E. Hogge
From the Terry Fox Laboratory, British Columbia Cancer
Agency, and the Departments of Medicine and Pathology and Laboratory
Medicine, University of British Columbia, Vancouver,
Canada.
Although many acute myeloid leukemia (AML) colony-forming cells
(CFCs) and long-term culture-initiating cells (LTC-ICs) directly isolated from patients are actively cycling, quiescent progenitors are
present in most samples. In the current study,
3H-thymidine (3H-Tdr) suicide assays
demonstrated that most NOD/SCID mouse leukemia-initiating cells
(NOD/SL-ICs) are quiescent in 6 of 7 AML samples. AML cells in
G0, G1, and S/G2+M were isolated
from 4 of these samples using Hoechst 33342/pyroninY staining and cell
sorting. The progenitor content of each subpopulation was consistent
with the 3H-Tdr suicide results, with NOD/SL-ICs found
almost exclusively among G0 cells while the cycling status
of AML CFCs and LTC-ICs was more heterogeneous. Interestingly, after 72 hours in serum-free culture with or without Steel factor (SF), Flt-3
ligand (FL), and interleukin-3 (IL-3), most G0 AML cells
entered active cell cycle (percentage of AML cells remaining in
G0 at 72 hours, 1.2% to 37%, and 0% to 7.6% in cultures
without and with growth factors [GFs], respectively) while
G0 cells from normal lineage-depleted bone marrow
remained quiescent in the absence of GF. All 4 AML samples showed
evidence of autocrine production of 2 or more of SF, FL, IL-3, and
granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition,
3 of 4 samples contained an internal tandem duplication of the
FLT3 gene. In summary, quiescent leukemic cells, including
NOD/SL-ICs, are present in most AML patients. Their spontaneous entry
into active cell cycle in short-term culture might be explained by the
deregulated GF signaling present in many AMLs.
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