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A triggering event is identified in the transformation of a precancerous cell to a cancer stem cell

 
  January, 23 2008 8:08
your information resource in human molecular genetics
 
     
Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Hong, D., Gupta, R., Ancliff, P., et al. Science, 319, 336-339 (January 18, 2008).

Acute lymphoblastic leukemia (ALL), which strikes during childhood, is often associated with a chromosomal translocation that creates the TEL-AML1 fusion gene. This event, which primarily occurs in utero, gives rise to a preleukemic clone that has been believed to convert to a self-renewing leukemic cell line.

The present study first focused on a rare population of CD34+CD38(-/low)CD19+ cells isolated from TEL-AML1-positive ALL patients. Their leukemogenic potential was demonstrated via engraftment into nonobese diabetic, severe combined immunodeficient (NOD/SCID) mice. Secondary grafts were also successful, indicating that the CD34+CD38(-/low)CD19+ cells are self-renewing cancer stem cells.

The events that transpire between creation of the TEL-AML1 fusion gene and transformation into leukemic stem cells was investigated in monochorionic twins, since these embryos share a placenta that may permit the migration of a preleukemic clone from one to the other. A pair of twins was identified in which one child developed leukemia at the age of two, while the other remained healthy. The peripheral blood of the healthy child contained a population of CD34+CD38(-/low)CD19+ cells at a very low frequency (0.002% of total mononuclear cells). Progenitor B cells did not experess TEL-AML1 transcripts, nor did more primitive multipotent stem cells that also did not express the B-lineage marker CD19. An analysis of IgH gene rearrangements of the healthy twin’s CD34+CD38(-low)CD19+ cells suggested that they were a clonally expanded population and that the fusion gene arose or had first functional impact in a cell that had already undergone recombination at the diversity and joining loci of the IgH gene. An analysis of the leukemic child’s CD34+CD38(-/low)CD19+ cells suggested that they were a descendent of the similar cells found in the healthy child.

A xenograft model was create by transplanting TEL-AML1 transduced human cord blood cells into NOD/SCID mice. The CD34+CD38(-/low)CD19+ cells displayed diversity and joining loci rearrangements in the IgH gene, but did not express CD10, thus resembling cells isolated from the healthy twin. They demonstrated self-renewal potential in vitro and engrafted in NOD/SCID mice, while also giving rise to more mature B cells (CD38+CD19+). The TEL-AML1-generated CD34+CD38(-/low)CD19+ cells have the capacity for self-renewal in vivo, suggesting that the fusion gene is sufficient to generate preleukemic stem cells.

This research has created a xenograft model that may serve as a tool for further examination of genetic alterations cooperating with the TEL-AML1 fusion gene. And the results offer an explanation of how surviving preleukemic stem cells may cause a relapse in a patient whose disease appeared to have been successfully treated.


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