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Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia.
- Source :
- Leukemia (08876924); Dec2012, Vol. 26 Issue 12, p2508-2516, 9p, 1 Chart, 6 Graphs
- Publication Year :
- 2012
-
Abstract
- Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in the elderly of the Western world. Although treatment options have improved over the past two decades, 10-15% of patients still have a poor prognosis and are often resistant to therapy. Aberrations in the p53 pathway, such as a deleted (del17p13) or mutated p53 gene, are highly enriched in this class of patients. In an extensive screen for p53-independent apoptosis inducers, actinomycin D was identified from 1496 substances and shown to induce apoptosis in primary CLL cells derived from high-risk patients including those with aberrant p53, revealing a novel p53-independent mechanism of action. Both pro-survival genes BCL2 and MCL1 are targeted by actinomycin D, in contrast to fludarabine the backbone of current treatment schedules. In the well-established TCL1 transgenic mouse model for high-risk CLL, actinomycin D treatment was more effective in reducing tumor load than fludarabine, with no evidence of resistance after three treatment cycles and an overall survival increase of over 300%. Tumor load reduction was coupled to BCL2 downregulation. Our results identify the clinically approved compound actinomycin D as a potentially valuable treatment option for CLL high-risk patients. [ABSTRACT FROM AUTHOR]
- Subjects :
- ACTINOMYCIN
CELL death
CHRONIC lymphocytic leukemia
APOPTOSIS
TRANSGENIC mice
Subjects
Details
- Language :
- English
- ISSN :
- 08876924
- Volume :
- 26
- Issue :
- 12
- Database :
- Complementary Index
- Journal :
- Leukemia (08876924)
- Publication Type :
- Academic Journal
- Accession number :
- 84140214
- Full Text :
- https://doi.org/10.1038/leu.2012.147