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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2808-2816
NEOPLASIA
Establishment of a murine model for therapy-treated chronic
myelogenous leukemia using the tyrosine kinase inhibitor
STI571
Nicholas C. Wolff and
Robert L. Ilaria Jr
From the Division of Hematology/Oncology, Department of
Medicine, Simmons Cancer Center, and the Hamon Center for Therapeutic
Oncology Research, University of Texas Southwestern Medical Center,
Dallas, TX.
The murine bone marrow retroviral transduction and transplantation
model of chronic myelogenous leukemia (CML) imperfectly mimics human
CML because the murine CML-like disease causes death of all animals
from an overwhelming granulocytosis within 3 to 4 weeks. In this
report, mice reconstituted with
P210BCR/ABL-transduced bone
marrow cells received posttransplantation therapy with either the
tyrosine kinase inhibitor STI571 or placebo. Compared with the rapidly
fatal leukemia of placebo-treated animals, 80% of the STI571-treated
mice were alive on day 74, with marked improvement in peripheral white
blood counts and splenomegaly. There was decreased tyrosine
phosphorylation of STAT5, Shc, and Crk-L in leukemic cells from
STI571-treated animals, consistent with STI571-mediated inhibition of
the Bcr/Abl tyrosine kinase in vivo. In some STI571-treated animals
Bcr/Abl messenger RNA and protein expression were markedly increased. In contrast to the polyclonal leukemia of placebo-treated mice, STI571-treated murine CML was generally oligoclonal, suggesting that STI571 eliminated or severely suppressed certain leukemic clones.
None of the STI571-treated mice were cured of the CML-like myeloproliferative disorder, however, and STI571-treated murine CML was
transplanted to secondary recipients with high efficiency. These
results demonstrate the utility of this murine model of CML in the
evaluation of novel therapeutic agents against Bcr/Abl-induced leukemias. This improved murine chronic-phase CML model may be a useful
tool for the study of STI571 resistance, CML progression, and the
anti-CML immune response.
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