Abstract
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aminoquinolines / pharmacology
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Animals
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Antigens, CD34 / biosynthesis
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Fusion Proteins, bcr-abl / metabolism*
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Gene Expression Regulation, Leukemic*
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Hematopoietic Stem Cells / metabolism
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy
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Mice
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Myeloproliferative Disorders / genetics*
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Myeloproliferative Disorders / metabolism*
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Myeloproliferative Disorders / therapy
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Neoplasm Transplantation
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Phenotype
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Pyrimidines / pharmacology
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RAC2 GTP-Binding Protein
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rac GTP-Binding Proteins / metabolism
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rac GTP-Binding Proteins / physiology*
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rac1 GTP-Binding Protein / metabolism
Substances
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Aminoquinolines
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Antigens, CD34
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NSC 23766
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Pyrimidines
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RAC1 protein, human
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Fusion Proteins, bcr-abl
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rac GTP-Binding Proteins
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rac1 GTP-Binding Protein