GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis

Cancer Cell. 2010 Jun 15;17(6):597-608. doi: 10.1016/j.ccr.2010.04.024.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CREB-Binding Protein / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic / physiology*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / prevention & control
  • Maleimides / pharmacology
  • Maleimides / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Oncogene Proteins, Fusion / genetics
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology*

Substances

  • CRTC1 protein, human
  • CRTC2 protein, human
  • Cdx4 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • HOXB1 homeodomain protein
  • Homeodomain Proteins
  • Hoxb4 protein, mouse
  • Indoles
  • MEIS1 protein, human
  • Maleimides
  • Meis1 protein, mouse
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Pbx1 protein, mouse
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • SB 216763
  • Transcription Factors
  • homeobox protein HOXA9
  • PBX1 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • CREB-Binding Protein
  • Glycogen Synthase Kinase 3

Associated data

  • GEO/GSE21842