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Blood, 1 February 2001, Vol. 97, No. 3, pp. 720-728
NEOPLASIA
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
Tessa L. Holyoake,
Xiaoyan Jiang,
Heather G. Jorgensen,
Susan Graham,
Michael J. Alcorn,
Chris Laird,
Allen C. Eaves, and
Connie J. Eaves
From Academic Transfusion Medicine Unit, Department of
Medicine, Royal Infirmary, Glasgow, United Kingdom; the Terry Fox
Laboratory, British Columbia Cancer Agency, Vancouver, Canada; and the
Departments of Medicine, Pathology, and Laboratory Medicine and Medical
Genetics, University of British Columbia, Vancouver, Canada.
It was previously shown that patients with chronic myeloid leukemia
(CML) have a rare but consistently detectable population of
quiescent (G0) leukemic (Philadelphia chromosome-positive
and BCR-ABL-positive [BCR-ABL+])
CD34+ cells. In the study described here, most such cells
expressed a primitive phenotype (CD38 ,
CD45RA, CD71, and HLA-DRlo) and
cultures of these cells containing growth factors produced ultimately larger, but initially more slowly growing clones than do
cultures of initially cycling CD34+ leukemic cells.
Initially quiescent leukemic cells expressing BCR-ABL
proliferated in single-cell cultures in the absence of added
growth factors, thereby demonstrating their ability to
spontaneously exit G0 and enter a continuously cycling
state. Interestingly, on isolation, few of these quiescent
BCR-ABL+ cells contained either
interleukin-3 (IL-3) or granulocyte colony-stimulating factor
(G-CSF) transcripts, whereas both were present in most cycling
BCR-ABL+ CD34+ cells.
However, after 4 days of culture in the absence of added growth
factors and in association with their entry into the cell cycle (as
indicated by up-regulation of Ki-67 and cdc25 transcripts), IL-3
transcripts became detectable. These findings show that entry of
leukemic (BCR-ABL-expressing) progenitors into a quiescent (G0) state in vivo is highest among the most primitive
leukemic cell populations, associated with a down-regulation of
IL-3 and G-CSF gene expression, and spontaneously reversible in
association with up-regulation of IL-3 expression. These results
highlight the potential physiologic relevance of quiescent CML
progenitors, even in treated patients, in whom these cells would be
predicted to have a proliferative advantage over their quiescent normal counterparts when cytokine concentrations are low.
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