A CHAF1B-Dependent Molecular Switch in Hematopoiesis and Leukemia Pathogenesis

Cancer Cell. 2018 Nov 12;34(5):707-723.e7. doi: 10.1016/j.ccell.2018.10.004.

Abstract

CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of histones H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro-leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele is sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis.

Keywords: CAF1; CHAF1B; MLL-AF9; hematopoiesis.

Publication types

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

MeSH terms

  • Adult
  • Animals
  • Binding Sites / physiology
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Chromatin / metabolism*
  • Chromatin Assembly Factor-1 / genetics
  • Chromatin Assembly Factor-1 / metabolism*
  • Exoribonucleases
  • Female
  • Hematopoiesis / genetics
  • Hematopoiesis / physiology*
  • Humans
  • Jurkat Cells
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleosomes / metabolism*
  • Protein Binding / physiology
  • Proteins / genetics
  • Proteins / metabolism*
  • Repressor Proteins
  • Ribonucleases

Substances

  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, mouse
  • Chaf1b protein, mouse
  • Chromatin
  • Chromatin Assembly Factor-1
  • Nucleosomes
  • Proteins
  • Repressor Proteins
  • Cnot7 protein, mouse
  • Exoribonucleases
  • Ribonucleases