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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4325-4335
Most Acute Myeloid Leukemia Progenitor Cells With Long-Term
Proliferative Ability In Vitro and In Vivo Have the Phenotype
CD34+/CD71 /HLA-DR
A. Blair,
D.E. Hogge, and
H.J. Sutherland
From the Terry Fox Laboratory, British Columbia Cancer Agency,
Vancouver Hospital and Health Sciences Centre, and the Department of
Medicine, University of British Columbia, Vancouver, BC, Canada.
Acute myeloid leukemia (AML) occurs as the result of malignant
transformation in a hematopoietic progenitor cell, which proliferates to form an accumulation of AML blasts. Only a minority of these AML
cells are capable of proliferation in vitro, suggesting that AML cells
may be organized in a hierarchy, with only the most primitive of these
cells capable of maintaining the leukemic clone. To further investigate
this hypothesis, we have evaluated a strategy for purifying these
primitive cells based on surface antigen expression. As an in vitro
endpoint, we have determined the phenotype of AML progenitor cells
which are capable of producing AML colony-forming cells (CFU) for up to
8 weeks in suspension culture (SC) and compared the phenotype with that
of cells which reproduce AML in nonobese diabetic/severe combined
immunodeficiency (NOD/SCID) mice. AML cells were fluorescence-activated
cell sorted (FACS) for coexpression of CD34 and CD71, CD38,
and/or HLA-DR and the subfractions were assayed in vitro and in
vivo at various cell doses to estimate purification. While the majority
of primary AML CFU lacked expression of CD34, most cells capable of
producing CFU after 2 to 8 weeks in SC were
CD34+/CD71 . HLA-DR expression was
heterogeneous on cells producing CFU after 2 to 4 weeks.
However, after 6 to 8 weeks in SC, the majority of CFU were derived
from CD34+/HLA-DR cells. Similarly, the
majority of cells capable of long-term CFU production from SC were
CD34+/CD38. Most cells that were capable
of engrafting NOD/SCID mice were also
CD34+/CD71 and
CD34+/HLA-DR. Engraftment was not achieved
with CD34+/CD71+ or HLA-DR+
subfractions, however, in two patients, both the CD34+
and CD34 subfractions were capable of engrafting the
NOD/SCID mice. A three-color sorting strategy combining these antigens
allowed approximately a 2-log purification of these NOD/SCID leukemia initiating cells, with engraftment achieved using as few as 400 cells
in one experiment. Phenotyping studies suggest even higher purification
could be achieved by combining lack of CD38 expression with the
CD34+/CD71 or CD34+/HLA
DR phenotype. These results suggest that most AML cells
capable of long-term proliferation in vitro and in vivo share the
CD34+/CD71/HLA-DR phenotype
with normal stem cells. Our data suggests that in this group of
patients the leukemic transformation has occurred in a primitive
progenitor, as defined by phenotype, with some degree of subsequent
differentiation as defined by functional assays.
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