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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3792-3800
NEOPLASIA
Imatinib mesylate (STI571) inhibits growth of primitive malignant
progenitors in chronic myelogenous leukemia through reversal of
abnormally increased proliferation
Melissa S. Holtz,
Marilyn
L. Slovak,
Feiyu Zhang,
Charles L. Sawyers,
Stephen J. Forman, and
Ravi Bhatia
From the Division of Hematology and Bone Marrow
Transplantation and the Department of Cytogenetics, City of Hope
National Medical Center, Duarte, CA; and the Division of Hematology and
Oncology, University of California at Los Angeles, CA.
Imatinib mesylate (STI571) is a promising new treatment for chronic
myelogenous leukemia (CML). The effect of imatinib mesylate on
primitive malignant progenitors in CML has not been evaluated, and it
is not clear whether suppression of progenitor growth represents inhibition of increased proliferation, induction of apoptosis, or both.
We demonstrated here that in vitro exposure to concentrations of
imatinib mesylate usually achieved in patients (1-2 µM) for 96 hours
inhibited BCR/ABL-positive primitive progenitors (6-week long-term culture-initiating cells [LTCICs]) as well as committed progenitors (colony-forming cells [CFCs]). No suppression of
normal LTCICs and significantly less suppression of normal CFCs were observed. A higher concentration of imatinib mesylate (5 µM) did not
significantly increase suppression of CML or normal LTCICs but did
increase suppression of CML CFCs, and to a lesser extent, normal CFCs.
Analysis of cell division using the fluorescent dye carboxyfluorescein
diacetate succinimidyl ester indicated that imatinib mesylate
(1-2 µM) inhibits cycling of CML primitive
(CD34+CD38 ) and committed
(CD34+CD38+) progenitors to a much greater
extent than normal cells. Conversely, treatment with 1 to 2 µM
imatinib mesylate did not significantly increase the percentage of
cells undergoing apoptosis. Although a higher concentration of imatinib
mesylate (5 µM) led to an increase in apoptosis of CML cells,
apoptosis also increased in normal samples. In summary, at clinically
relevant concentrations, imatinib mesylate selectively suppresses CML
primitive progenitors by reversing abnormally increased proliferation
but does not significantly increase apoptosis. These results suggest
that inhibition of Bcr-Abl tyrosine kinase by imatinib mesylate
restores normal hematopoiesis by removing the proliferative advantage
of CML progenitors but that elimination of all CML progenitors may not occur.
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