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Fluorouracil selectively spares acute myeloid leukemia cells with long-
term growth abilities in immunodeficient mice and in culture
W Terpstra, RE Ploemacher, A Prins, K van Lom, K Pouwels, AW Wognum, G Wagemaker, B Lowenberg and JJ Wielenga
Institute of Hematology, Erasmus University, Rotterdam, The Netherlands.
A subset of leukemic cells is assumed to maintain long-term growth of acute
myeloid leukemia (AML) in vivo. Characterization of these AML progenitor
cells may further define growth properties of human leukemia. In vitro
incubations with 5-fluorouracil (5-FU) have been used for enrichment of
normal primitive hematopoietic stem cells. By analogy to normal
hematopoiesis, it was hypothesized that primitive leukemic stem cells might
be kinetically more inactive than colony- forming cells (colony-forming
units-AML [CFU-AML]). To examine this hypothesis, conditions were
established for incubation with 5-FU that eliminated all CFU-AML. These
conditions selected a 5-FU-resistant AML fraction that was evaluated for
its capacity for long-term growth by transplantation into mice with severe
combined immunodeficiency (SCID) and long-term culture in the quantitative
cobblestone area-forming cell (CAFC) assay. Transplantation of the
5-FU-resistant fraction of four cases of AML into SCID mice resulted in
growth of AML. Whereas no CFU- AML survived, 31% to 82% of primitive
(week-6) CAFC were recovered from the 5-FU-treated cells. Hematopoietic
cells proliferating in the CAFC assay were shown to be leukemic by
cytologic, cytogenetic, or molecular analysis. The reduction of AML growth
as determined by outgrowth of AML in SCID mice was in the same order of
magnitude as the primitive (week- 6) CAFC reduction. This indicates that
both assays measure closely related cell populations and that the CAFC
assay can be used to study long-term growth of AML. These results show a
hierarchy of AML cells that includes 5-FU-resistant progenitors. These
cells are characterized as primitive (week-6) CAFC and as
leukemia-initiating cells in SCID mice.
Volume 88,
Issue 6,
pp. 1944-1950,
09/15/1996
Copyright © 1996 by The American Society of Hematology
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