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• W2043692783 endingPage "1834" @default.
• W2043692783 startingPage "1823" @default.
• W2043692783 abstract "Disruption of the RAS–to–mitogen-activated protein kinase (MAPK/ERK) signaling pathway, either directly through activatingRAS 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 activatingRAS 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." @default.
• W2043692783 created "2016-06-24" @default.
• W2043692783 creator A5011083669 @default.
• W2043692783 creator A5050500238 @default.
• W2043692783 creator A5081076272 @default.
• W2043692783 date "2001-03-15" @default.
• W2043692783 modified "2023-10-16" @default.
• W2043692783 title "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" @default.
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• W2043692783 doi "https://doi.org/10.1182/blood.v97.6.1823" @default.
• W2043692783 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/11238126" @default.
• W2043692783 hasPublicationYear "2001" @default.
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