Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia

Blood. 2010 Apr 8;115(14):2872-81. doi: 10.1182/blood-2009-05-222836. Epub 2009 Oct 27.


Hairy enhancer of split 1 (Hes1) is a basic helix-loop-helix transcriptional repressor that affects differentiation and often helps maintain cells in an immature state in various tissues. Here we show that retroviral expression of Hes1 immortalizes common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) in the presence of interleukin-3, conferring permanent replating capability on these cells. Whereas these cells did not develop myeloproliferative neoplasms when intravenously administered to irradiated mice, the combination of Hes1 and BCR-ABL in CMPs and GMPs caused acute leukemia resembling blast crisis of chronic myelogenous leukemia (CML), resulting in rapid death of the recipient mice. On the other hand, BCR-ABL alone caused CML-like disease when expressed in c-Kit-positive, Sca-1-positive, and lineage-negative hematopoietic stem cells (KSLs), but not committed progenitors CMPs or GMPs, as previously reported. Leukemic cells derived from Hes1 and BCR-ABL-expressing CMPs and GMPs were more immature than those derived from BCR-ABL-expressing KSLs. Intriguingly, Hes1 was highly expressed in 8 of 20 patients with CML in blast crisis, but not in the chronic phase, and dominant negative Hes1 retarded the growth of some CML cell lines expressing Hes1. These results suggest that Hes1 is a key molecule in blast crisis transition in CML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Blast Crisis / genetics
  • Blast Crisis / metabolism*
  • Blast Crisis / pathology
  • Cell Line, Transformed
  • Fusion Proteins, bcr-abl / biosynthesis
  • Fusion Proteins, bcr-abl / genetics
  • Granulocyte-Macrophage Progenitor Cells / metabolism*
  • Granulocyte-Macrophage Progenitor Cells / pathology
  • Homeodomain Proteins / biosynthesis*
  • Homeodomain Proteins / genetics
  • Interleukin-3 / genetics
  • Interleukin-3 / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Rats
  • Repressor Proteins / biosynthesis*
  • Repressor Proteins / genetics
  • Transcription Factor HES-1


  • Basic Helix-Loop-Helix Transcription Factors
  • Hes1 protein, rat
  • Homeodomain Proteins
  • IL3 protein, human
  • Interleukin-3
  • Repressor Proteins
  • Transcription Factor HES-1
  • HES1 protein, human
  • Fusion Proteins, bcr-abl