Abstract
The tumor suppressor gene phosphatase and tensin homolog (PTEN) is inactivated in many human cancers. However, it is unknown whether PTEN functions as a tumor suppressor in human Philadelphia chromosome-positive leukemia that includes chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL) and is induced by the BCR-ABL oncogene. By using our mouse model of BCR-ABL-induced leukemias, we show that Pten is down-regulated by BCR-ABL in leukemia stem cells in CML and that PTEN deletion causes acceleration of CML development. In addition, overexpression of PTEN delays the development of CML and B-ALL and prolongs survival of leukemia mice. PTEN suppresses leukemia stem cells and induces cell-cycle arrest of leukemia cells. Moreover, PTEN suppresses B-ALL development through regulating its downstream gene Akt1. These results demonstrate a critical role of PTEN in BCR-ABL-induced leukemias and suggest a potential strategy for the treatment of Philadelphia chromosome-positive leukemia.
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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Animals
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cells, Cultured
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Disease Progression
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / physiology
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Gene Expression Regulation, Leukemic / physiology
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / mortality
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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PTEN Phosphohydrolase / physiology*
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Survival Analysis
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Transplantation, Heterologous
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Tumor Suppressor Proteins* / genetics
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Tumor Suppressor Proteins* / metabolism
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Tumor Suppressor Proteins* / physiology
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Up-Regulation / physiology
Substances
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Tumor Suppressor Proteins
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Fusion Proteins, bcr-abl
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PTEN Phosphohydrolase
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Pten protein, mouse