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Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells

Weili Chen1, Ashish R Kumar, Wendy A Hudson

  • 1University of Minnesota Cancer Center, University of Minnesota, 420 Delaware Street S.E., Minneapolis, MN 55455, USA.

Cancer Cell
|May 6, 2008
PubMed

Insights

Oncogene MLL-AF9 transforms hematopoietic stem cells but not committed progenitors, with dosage influencing leukemia development. This highlights cell-type specific oncogene effects in leukemia initiation.

Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • The precise mechanisms by which oncogenes drive transformation and leukemia remain incompletely understood.
  • Understanding the role of oncogene dosage and target cell type is crucial for defining leukemia pathogenesis.

Purpose of the Study:

  • To investigate the role of MLL-AF9 oncogene in transforming hematopoietic stem cells versus committed progenitors.
  • To determine the impact of MLL-AF9 oncogene dosage on leukemia initiation and development.

Main Methods:

  • Comparative analysis of MLL-AF9 transformation efficiency in LSK (Lin(-)Sca1(+)c-kit(+)) stem cells and granulocyte-monocyte progenitors (GMPs).
  • Assessment of MLL-AF9 expression levels in different hematopoietic cell populations.
  • Retroviral transduction to manipulate MLL-AF9 gene dosage in GMPs.
  • Gene expression profiling to identify MLL-AF9-regulated genes.

Main Results:

  • MLL-AF9 efficiently transformed LSK stem cells under endogenous control, while GMPs exhibited resistance.
  • Higher MLL-AF9 expression was observed in hematopoietic stem cells (HSCs) compared to GMPs.
  • High-dose MLL-AF9, introduced via retroviral transduction, efficiently transformed GMPs, leading to leukemia.
  • MLL-AF9 upregulated 192 genes in both LSK and progenitor cells, with greater upregulation in LSKs.

Conclusions:

  • Hematopoietic stem cell transformation by MLL-AF9 is dependent on the target cell type and oncogene dosage.
  • MLL-AF9 exhibits cell-type specific oncogenic activity, with HSCs being more susceptible than GMPs at endogenous levels.
  • Gene dosage is a critical factor in overcoming transformation resistance in committed myeloid progenitors, driving leukemia development.

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