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Etoposide induces chimeric Mll gene fusions.
Javier G Blanco1, Mathew J Edick, Mary V Relling
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Summary
Etoposide, a topoisomerase II inhibitor, significantly increases the occurrence of MLL gene fusions in mouse cells. This finding is crucial for understanding treatment-induced leukemias.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- MLL gene fusions are characteristic of over 70% of therapy-related leukemias (t-ML).
- Topoisomerase II inhibitors, like etoposide, are frequently associated with t-ML.
- MLL gene fusions are known to induce leukemia in murine models.
Purpose of the Study:
- To investigate if MLL gene fusions can be induced by exposure to topoisomerase II inhibitors.
- To quantify the frequency of MLL gene fusions after etoposide treatment.
Main Methods:
- Development of a long-distance inverse PCR DNA-based assay.
- Analysis of MLL fusions in mouse embryonic stem cells.
- Exposure of cells to etoposide and vincristine, with comparison to controls.
Main Results:
- Etoposide treatment significantly increased MLL fusion frequency (16x10^-6 cell^-1) compared to controls (1.0x10^-6 cell^-1).
- No significant increase in fusions was observed with vincristine treatment.
- Fusion points were localized to a specific region (exons 9-11) analogous to human MLL breakpoints.
- Identified Runx1 as a fusion partner, homologous to human AML-1.
Conclusions:
- Etoposide directly triggers the formation of MLL gene fusions.
- These fusions represent a critical step in the development of treatment-induced leukemia.
- The findings provide insight into the mechanism of therapy-related leukemogenesis.