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Blood, 15 January 2003, Vol. 101, No. 2, pp. 690-698
NEOPLASIA
BCR-ABL independence and LYN kinase overexpression in chronic
myelogenous leukemia cells selected for resistance to STI571
Nicholas J. Donato,
Ji Yuan Wu,
Jonathan Stapley,
Gary Gallick,
Hui Lin,
Ralph Arlinghaus, and
Moshe Talpaz
From the Departments of Bioimmunotherapy, Cancer
Biology, and Molecular Pathology, University of Texas, M D Anderson
Cancer Center, Houston, TX.
Clinical studies have shown that the tyrosine kinase inhibitor
STI571 effectively controls BCR-ABL-positive chronic myelogenous leukemia (CML). However, disease progression while on STI571 therapy has been reported, suggesting de novo or intrinsic resistance to
BCR-ABL-targeted therapy. To investigate possible mediators of
acquired STI571 resistance, K562 cells resistant to 5 µM STI571 (K562-R) were cloned and compared to the parental cell population. K562-R cells had reduced BCR-ABL expression and limited activation of
BCR-ABL signaling cascades (Stat 5, CrkL, MAPK). STI571 failed to
activate caspase cascades or to suppress expression of survival genes
(bcl-xL) in resistant cells. Gene sequencing and tyrosine kinase
activity measurements demonstrated that K562-R cells retained wild-type
and active BCR-ABL tyrosine kinase that was inhibitable by in vitro
incubation with STI571, suggesting that BCR-ABL was not coupled to
proliferation or survival of K562-R cells. The src-related kinase LYN
was highly overexpressed and activated in K562-R cells, and its
inhibition reduced proliferation and survival of K562-R cells while
having limited effects of K562 cells. Specimens taken from patients
with advanced CML that progressed on STI571 therapy also were analyzed
for LYN kinase expression, and they were found to be elevated to a
level similar to that of K562-R cells. Comparison of samples from
patients taken prior to and following STI571 failure suggested that
expression and/or activation of LYN/HCK occurs during disease
progression. Together, these results suggest that acquired STI571
resistance may be associated with BCR-ABL independence and mediated in
part through overexpression of other tyrosine kinases.
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