Clonal evolution of pre-leukemic hematopoietic stem cells precedes human acute myeloid leukemia

Best Pract Res Clin Haematol. 2014 Sep-Dec;27(3-4):229-34. doi: 10.1016/j.beha.2014.10.003. Epub 2014 Oct 15.


Massively parallel DNA sequencing has uncovered recurrent mutations in many human cancers. In acute myeloid leukemia (AML), cancer genome/exome resequencing has identified numerous recurrently mutated genes with an average of 5 mutations in each case of de novo AML. In order for these multiple mutations to accumulate in a single lineage of cells, they are serially acquired in clones of self-renewing hematopoietic stem cells (HSC), termed pre-leukemic HSC. Isolation and characterization of pre-leukemic HSC have shown that their mutations are enriched in genes involved in regulating DNA methylation, chromatin modifications, and the cohesin complex. On the other hand, genes involved in regulating activated signaling are generally absent. Pre-leukemic HSC have been found to persist in clinical remission and may ultimately give rise to relapsed disease through the acquisition of novel mutations. Thus, pre-leukemic HSC may constitute a key cellular reservoir that must be eradicated for long-term cures.

Keywords: acute myeloid leukemia; clonal evolution; hematopoietic stem cells (HSC); pre-leukemic HSC.

Publication types

  • Review

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Methylation
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Mutation
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA, Neoplasm
  • cohesins