Abstract
We show constitutive activation of Rho kinase (ROCK) in cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL, which is dependent on PI3K and Rho GTPase. Genetic or pharmacologic inhibition of ROCK in oncogene-bearing cells impaired their growth as well as the growth of acute myeloid leukemia patient-derived blasts and prolonged the life span of mice bearing myeloproliferative disease. Downstream from ROCK, rapid dephosphorylation or loss of expression of myosin light chain resulted in enhanced apoptosis, reduced growth, and loss of actin polymerization in oncogene-bearing cells leading to significantly prolonged life span of leukemic mice. In summary we describe a pathway involving PI3K/Rho/ROCK/MLC that may contribute to myeloproliferative disease and/or acute myeloid leukemia in humans.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Animals
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Apoptosis / genetics
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival
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Cell Transformation, Neoplastic*
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Fusion Proteins, bcr-abl / biosynthesis
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism*
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Humans
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Leukemia / metabolism*
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Leukemia / mortality
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Leukemia / pathology
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Leukemia, Myeloid, Acute / metabolism*
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Leukemia, Myeloid, Acute / mortality
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Leukemia, Myeloid, Acute / pathology
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Myeloproliferative Disorders / metabolism*
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Myeloproliferative Disorders / mortality
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Myeloproliferative Disorders / pathology
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Myosin Light Chains / biosynthesis
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Myosin Light Chains / genetics
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Myosin Light Chains / metabolism
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Phosphatidylinositol 3-Kinases / biosynthesis
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Phosphorylation
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Protein-Tyrosine Kinases / biosynthesis
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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RNA Interference
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RNA, Small Interfering
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Signal Transduction / genetics
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Stem Cell Factor / biosynthesis
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Stem Cell Factor / genetics
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Stem Cell Factor / metabolism*
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fms-Like Tyrosine Kinase 3 / biosynthesis
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fms-Like Tyrosine Kinase 3 / genetics
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fms-Like Tyrosine Kinase 3 / metabolism*
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rho GTP-Binding Proteins / biosynthesis
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rho-Associated Kinases / antagonists & inhibitors
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rho-Associated Kinases / genetics
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rho-Associated Kinases / metabolism*
Substances
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Actins
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Myosin Light Chains
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RNA, Small Interfering
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Stem Cell Factor
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Phosphatidylinositol 3-Kinases
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FLT3 protein, human
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Protein-Tyrosine Kinases
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fms-Like Tyrosine Kinase 3
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Fusion Proteins, bcr-abl
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rho-Associated Kinases
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rho GTP-Binding Proteins