| p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells. | |
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MedLine Citation:
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PMID: 21350558 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Philadelphia chromosome positive chronic myeloid leukemia has a progressive course starting in a benign phase and terminating in a blastic phase. In this study, we show that human homolog double minute 2 (HDM2) inhibition, with MI-219-a novel compound, and consequently p53 stabilization induce chronic myeloid leukemia (CML) blast crisis cells to undergo apoptosis regardless of the presence of the T315I mutation in the BCR-ABL kinase domain. The response to MI-219 is associated with the downregulation of c-Myc and the induction of p21(WAF1). The p53 target and pro-apoptotic proteins PUMA, Noxa and Bax are induced, whereas full length Bid protein decreases with increased activity of pro-apoptotic cleaved Bid, and decrease of Mcl-1 is observed by increased caspase activity. CD95/FAS (FAS antigen) receptor is also induced by MI-219, indicating that both intrinsic and extrinsic apoptotic responses are transcriptionally induced. In addition, p53 protein accumulates in the mitochondrial fraction of treated cells involved in transcription-independent induction of apoptosis. We conclude that HDM-2 inhibition with MI-219 effectively induces p53-dependent apoptosis in most blast crisis CML cells, with or without BCR-ABL mutation(s).Leukemia advance online publication, 25 February 2011; doi:10.1038/leu.2011.7. |
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Authors:
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L F Peterson; E Mitrikeska; D Giannola; Y Lui; H Sun; D Bixby; S N Malek; N J Donato; S Wang; M Talpaz |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-2-25 |
Journal Detail:
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Title: Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K Volume: - ISSN: 1476-5551 ISO Abbreviation: - Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-2-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8704895 Medline TA: Leukemia Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA [2] Department of Internal Medicine Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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