CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis

Cancer Cell. 2011 Nov 15;20(5):563-75. doi: 10.1016/j.ccr.2011.09.008.

Abstract

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene lead to the development of acute leukemias. Constitutive HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Transformation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Hematopoiesis / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Leukemia / genetics*
  • Mice
  • Mitochondrial Membrane Transport Proteins
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Myeloid-Lymphoid Leukemia Protein / physiology
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / physiology
  • Point Mutation
  • Polycomb Repressive Complex 1
  • Polycomb-Group Proteins
  • Protein Interaction Mapping
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Repressor Proteins / physiology*
  • Sequence Alignment
  • Translocation, Genetic

Substances

  • CBX8 protein, human
  • Homeodomain Proteins
  • MLL-AF9 fusion protein, human
  • MLL-AF9 fusion protein, mouse
  • Mitochondrial Membrane Transport Proteins
  • Oncogene Proteins, Fusion
  • Polycomb-Group Proteins
  • Repressor Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Cbx8 protein, mouse
  • Polycomb Repressive Complex 1