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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1823-1834
NEOPLASIA
Cell-cycle-dependent activation of mitogen-activated
protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and
induction of growth inhibition and apoptosis by inhibitors of
RAS signaling
Michael A. Morgan,
Oliver Dolp, and
Christoph W. M. Reuter
From the Department of Hematology and Oncology, Section
Molecular Biology, University of Ulm, Germany.
Disruption of the RAS-to-mitogen-activated protein
kinase (MAPK/ERK) signaling pathway, either directly through activating RAS gene mutations or indirectly through other genetic
aberrations, plays an important role in the molecular pathogenesis of
myeloid leukemias. Constitutive activation of ERK-1/2 and MEK-1/2,
which elicit oncogenic transformation in fibroblasts, has recently been observed in acute myeloid leukemias (AML). In this study, the activation of the RAS-to-MAPK cascade in 14 AML and 5 chronic myeloid
leukemia (CML) cell lines is examined and correlated with the effects
of a panel of 9 RAS signaling inhibitors on cell viability, colony
formation, cell-cycle progression, and induction of apoptosis. Activation of MEK, ERK, and the transcription factors CREB-1, ATF-1,
and c-Myc is demonstrated in the majority of the cell lines (9 of 14 AML and 2 of 5 CML cell lines). Although activation of the ERK cascade
did not always correlate with the presence of activating
RAS mutations or BCR-Abl, it is linked to the
G0/G1 and the G2/M phase of the
cell cycle. In contrast to most inhibitors (eg, B581, Cys-4-Abs-Met,
FPT-2, FTI-276, and FTS), a significant growth inhibition was only
observed for FTI-277 (19 of 19), FPT-3 (10 of 19), and the MEK
inhibitors U0126 (19 of 19) and PD098059 (8 of 19). Treatment of NB-4
cells with FTI-277 primarily resulted in a G2/M block,
whereas treatment with FPT-3 and U0126 led to induction of apoptosis.
FTI-277 revealed strong toxicity toward normal purified
CD34+ cells. The results suggest differences in the
mechanisms of action and support a potential therapeutic usefulness of
these inhibitors in the treatment of myeloid leukemias.
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