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Phenotypic heterogeneity of primitive leukemic hematopoietic cells in
patients with chronic myeloid leukemia
C Udomsakdi, CJ Eaves, PM Lansdorp and AC Eaves
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
The peripheral blood of chronic myeloid leukemia (CML) patients with
chronic-phase disease and elevated white blood cell (WBC) counts typically
contains markedly increased numbers of a variety of neoplastic pluripotent
and lineage-restricted hematopoietic progenitors. These include cells
detected in standard colony assays as well as their more primitive
precursors. The latter are referred to as long-term culture-initiating
cells (LTC-IC) because of their ability to generate clonogenic cell progeny
detectable after a minimum of 5 weeks incubation on competent fibroblast
feeder layers. In this study, we have investigated a number of the
properties of the LTC-IC and clonogenic cells present in the blood of such
CML patients with high WBC counts. This included an analysis of the light
scattering properties of these progenitors, as well as their expression of
CD34 and HLA-DR, Rhodamine-123 staining, and in vitro sensitivity to 4-
hydroperoxycyclophosphamide. In the case of LTC-IC, the production of
different types of lineage-restricted and multipotent progeny was also
analyzed. Most of the circulating LTC-IC and clonogenic cells in the CML
patients studied (on average approximately 70% and approximately 90%,
respectively) showed features of proliferating or activated cells. This is
in marked contrast to the majority of progenitors in the blood of normal
individuals and most of the LTC-IC in normal marrow, all of which exhibit a
phenotype expected of quiescent cells. Interestingly, a significant
proportion of the circulating clonogenic cells and LTC-IC in the CML
samples studied (on average approximately 10% and approximately 30%,
respectively) appeared to be phenotypically similar to normal circulating
progenitors, although their absolute numbers were indicative of a
neoplastic origin. Both phenotypes of circulating CML clonogenic cells and
LTC-IC could be obtained at approximately 10% to 20% purity by differential
multiparameter sorting. These findings suggest that expansion of the
Philadelphia chromosome-positive clone at the level of the earliest types
of hematopoietic cells results from the activation of mechanisms that
enable some, but not all, signals that block the cycling of normal stem
cells to be bypassed or overcome. In addition, they provide strategies for
purifying these primitive leukemic cells that should facilitate further
analysis of the mechanisms underlying their abnormal proliferative
behavior.
Volume 80,
Issue 10,
pp. 2522-2530,
11/15/1992
Copyright © 1992 by The American Society of Hematology
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