Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells

Nat Commun. 2016 Jul 11;7:12166. doi: 10.1038/ncomms12166.

Abstract

The precise identity of a tumour's cell of origin can influence disease prognosis and outcome. Methods to reliably define tumour cell of origin from primary, bulk tumour cell samples has been a challenge. Here we use a well-defined model of MLL-rearranged acute myeloid leukaemia (AML) to demonstrate that transforming haematopoietic stem cells (HSCs) and multipotent progenitors results in more aggressive AML than transforming committed progenitor cells. Transcriptome profiling reveals a gene expression signature broadly distinguishing stem cell-derived versus progenitor cell-derived AML, including genes involved in immune escape, extravasation and small GTPase signal transduction. However, whole-genome profiling of open chromatin reveals precise and robust biomarkers reflecting each cell of origin tested, from bulk AML tumour cell sampling. We find that bulk AML tumour cells exhibit distinct open chromatin loci that reflect the transformed cell of origin and suggest that open chromatin patterns may be leveraged as prognostic signatures in human AML.

Publication types

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

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic
  • Chromatin Assembly and Disassembly*
  • Epigenesis, Genetic
  • Female
  • HEK293 Cells
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / metabolism
  • Mice, Inbred C57BL
  • Multipotent Stem Cells / metabolism
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Oncogene Proteins, Fusion / genetics
  • Transcriptome

Substances

  • MLL-AF9 fusion protein, human
  • MLL-AF9 fusion protein, mouse
  • Oncogene Proteins, Fusion
  • Myeloid-Lymphoid Leukemia Protein