Abstract
Mutations in KIT and TET2 are associated with myeloid malignancies. We show that loss of TET2-induced PI3K activation and -increased proliferation is rescued by targeting the p110α/δ subunits of PI3K. RNA-Seq revealed a hyperactive c-Myc signature in Tet2-/- cells, which is normalized by inhibiting PI3K signaling. Loss of TET2 impairs the maturation of myeloid lineage-derived mast cells by dysregulating the expression of Mitf and Cebpa, which is restored by low-dose ascorbic acid and 5-azacytidine. Utilizing a mouse model in which the loss of TET2 precedes the expression of oncogenic Kit, similar to the human disease, results in the development of a non-mast cell lineage neoplasm (AHNMD), which is responsive to PI3K inhibition. Thus, therapeutic approaches involving hypomethylating agents, ascorbic acid, and isoform-specific PI3K inhibitors are likely to be useful for treating patients with TET2 and KIT mutations.
Keywords:
Cancer; Hematology; Hematopoietic stem cells.
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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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / pathology
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DNA Methylation / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dioxygenases
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Disease Models, Animal
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Epigenesis, Genetic*
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Gain of Function Mutation
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics*
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Gene Knock-In Techniques
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Humans
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Mast Cells / pathology*
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Mastocytosis / drug therapy
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Mastocytosis / genetics*
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Mastocytosis / pathology
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Mice
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Mice, Knockout
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Myeloid Cells / drug effects
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Myeloid Cells / physiology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism*
Substances
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Antineoplastic Agents
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DNA-Binding Proteins
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Kit protein, mouse
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Dioxygenases
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Tet2 protein, mouse
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Proto-Oncogene Proteins c-kit