Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

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, suc...

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Bibliographic Details
Published in:	Leukemia Vol. 26; no. 12; pp. 2508 - 2516
Main Authors:	Merkel, O, Wacht, N, Sifft, E, Melchardt, T, Hamacher, F, Kocher, T, Denk, U, Hofbauer, J P, Egle, A, Scheideler, M, Schlederer, M, Steurer, M, Kenner, L, Greil, R
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-12-2012 Nature Publishing Group
Subjects:	631/80/82/23 692/699/67/1059/99 692/699/67/1990/283/1895 Actinomycin Analysis Animal experimentation Animals Antibiotics, Antineoplastic - therapeutic use Antineoplastic Agents - therapeutic use Apoptosis Apoptosis - drug effects Biological and medical sciences Blotting, Western Cancer Research Care and treatment Cell death Cell survival Chronic lymphocytic leukemia Critical Care Medicine Dactinomycin Dactinomycin - therapeutic use Female Flow Cytometry Fludarabine Genetic aspects Health aspects Hematologic and hematopoietic diseases Hematology Humans Intensive Internal Medicine Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - mortality Leukemia, Lymphocytic, Chronic, B-Cell - pathology Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphatic leukemia Male Malignancy Mcl-1 protein Medical prognosis Medical sciences Medicine Medicine & Public Health Mice Mice, Inbred C57BL Mice, SCID Mice, Transgenic Myeloid Cell Leukemia Sequence 1 Protein Oncology original-article p53 Protein Patients Physiological aspects Prognosis Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Risk groups RNA, Messenger - genetics Survival Survival Rate Transgenic mice Tumor Cells, Cultured Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors Vidarabine - analogs & derivatives Vidarabine - therapeutic use BCL2 actinomycin D CLL del17p mouse model MCL1 Actinomycin Animal model High risk TP53 Gene Lymphoproliferative syndrome Protooncogene Tumor suppressor gene Cell survival Hematology Rodentia Malignant hemopathy Vertebrata Chronic lymphocytic leukemia Mammalia Apoptosis inhibitory protein Mouse MCL1 gene Cell death C-Onc gene Cancer Apoptosis Prolonged
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0887-6924 1476-5551
DOI:	10.1038/leu.2012.147