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Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
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A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology.

M Metzler1, A Forster, R Pannell

  • 1MRC Laboratory of Molecular Biology, Cambridge, UK.

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|April 12, 2006
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The MLL-AF4 fusion protein drives infant leukemia but isn't essential in stem cells. This study shows MLL-AF4 instructs the specific cancer cell type, not initial development.

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Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Chromosomal translocations involving MLL and AF4 are common in infant leukemia, leading to poor prognosis.
  • The MLL-AF4 fusion protein's role in initiating leukemia and specifying B-cell tumors is not fully understood.

Purpose of the Study:

  • To investigate the necessity of MLL-AF4 in hematopoietic stem cells for leukemia development.
  • To determine if MLL-AF4 plays an instructive role in determining the tumor cell phenotype.

Main Methods:

  • Utilized invertor conditional technology to create a mouse model with a floxed AF4 cDNA knocked into the Mll gene.
  • Generated MLL-AF4 expression using cell-specific Cre recombinase.
  • Analyzed the resulting neoplasms in mice.

Main Results:

  • Mice exclusively developed B-cell lineage neoplasias, irrespective of the Cre promoter (B-cell or T-cell).
  • The observed B-cell neoplasms exhibited a more mature phenotype than typical childhood leukemia.
  • MLL-AF4 expression was not mandatory in multi-potent hematopoietic stem cells for cancer initiation.

Conclusions:

  • The MLL-AF4 fusion protein does not require a role in multi-potent hematopoietic stem cells to initiate leukemia.
  • MLL-AF4 plays an instructive role in specifying the phenotype of the resulting B-cell tumors.