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.
Pubmed ID: 20541704 RIS Download
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