JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis.
Linda S. Steelman,Steven C. Pohnert,John G. Shelton,Richard A. Franklin,Fred E. Bertrand,James A. McCubrey +5 more
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TLDR
This review will tie together three important signal transduction pathways involved in the regulation of hematopoietic cell growth and indicate how their expression is dysregulated by the BCR-ABL oncoprotein.Abstract:
The roles of the JAK/STAT, Raf/MEK/ERK and PI3K/Akt signal transduction pathways and the BCR-ABL oncoprotein in leukemogenesis and their importance in the regulation of cell cycle progression and apoptosis are discussed in this review. These pathways have evolved regulatory proteins, which serve to limit their proliferative and antiapoptotic effects. Small molecular weight cell membrane-permeable drugs that target these pathways have been developed for leukemia therapy. One such example is imatinib mesylate, which targets the BCR-ABL kinase as well as a few structurally related kinases. This drug has proven to be effective in the treatment of CML patients. However, leukemic cells have evolved mechanisms to become resistant to this drug. A means to combat drug resistance is to target other prominent signaling components involved in the pathway or to inhibit BCR-ABL by other mechanisms. Treatment of imatinib-resistant leukemia cells with drugs that target Ras (farnysyl transferase inhibitors) or with the protein destabilizer geldanamycin has proven to be a means to inhibit the growth of resistant cells. This review will tie together three important signal transduction pathways involved in the regulation of hematopoietic cell growth and indicate how their expression is dysregulated by the BCR-ABL oncoprotein.read more
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Roles of the raf/mek/erk pathway in cell growth, malignant transformation and drug resistance
James A. McCubrey,Linda S. Steelman,William H. Chappell,Stephen L. Abrams,Ellis W.T. Wong,Fumin Chang,Brian D. Lehmann,David M. Terrian,Michele Milella,Agostino Tafuri,Franca Stivala,Massimo Libra,Jörg Bäsecke,Camilla Evangelisti,Alberto M. Martelli,Richard A. Franklin +15 more
TL;DR: The Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors.
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FDA-approved small-molecule kinase inhibitors
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Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia.
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