GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.
Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and ... CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias.
Mesh Terms:
Animals, CREB-Binding Protein, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Cyclic AMP Response Element-Binding Protein, DNA-Binding Proteins, Down-Regulation, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Glycogen Synthase Kinase 3, Homeodomain Proteins, Humans, Indoles, Leukemia, Myeloid, Acute, Maleimides, Mice, Mice, Inbred C57BL, Models, Biological, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins, Neoplastic Stem Cells, Oncogene Proteins, Fusion, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-fos, Signal Transduction, Transcription Factors, Transcription, Genetic
Animals, CREB-Binding Protein, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Cyclic AMP Response Element-Binding Protein, DNA-Binding Proteins, Down-Regulation, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Glycogen Synthase Kinase 3, Homeodomain Proteins, Humans, Indoles, Leukemia, Myeloid, Acute, Maleimides, Mice, Mice, Inbred C57BL, Models, Biological, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins, Neoplastic Stem Cells, Oncogene Proteins, Fusion, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-fos, Signal Transduction, Transcription Factors, Transcription, Genetic
Cancer Cell
Date: Jun. 15, 2010
PubMed ID: 20541704
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