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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1584-1593. Prepublished online as a Blood First Edition Paper on October 30, 2007; DOI 10.1182/blood-2007-09-112698. This Article Full Text Full Text (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2007-09-112698v1 111/3/1584    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Saddler, C. Articles by Malek, S. N. Search for Related Content PubMed PubMed Citation Articles by Saddler, C. Articles by Malek, S. N. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia Chris Saddler1, Peter Ouillette1, Lisa Kujawski1, Sanjeev Shangary1, Moshe Talpaz1, Mark Kaminski1, Harry Erba1, Kerby Shedden2, Shaomeng Wang1, and Sami N. Malek1 1 Department of Internal Medicine, Division of Hematology and Oncology; and 2 Department of Statistics, University of Michigan, Ann Arbor Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and remains incurable with conventional therapies. Patients with relapsed or resistant CLL have a significantly shortened lifespan. MDM2 inhibitors have been developed and may have significant potential in the treatment of CLL. Clinical development of these compounds would be aided through knowledge of molecular predictors of activity. To understand determinants of sensitivity or resistance to MDM2 inhibitor therapy in CLL, we comprehensively analyzed a large cohort of CLL patient–derived samples for response to MDM2 inhibition and correlated these responses with clinically important biomarkers. Furthermore, we employed high-density single nucleotide polymorphism (SNP) arrays to analyze genomewide changes of copy number and allele status, including that of p53. The results of these studies conclusively demonstrate that p53 status is the major determinant of response to MDM2 inhibitors in CLL. Additional defects in the p53 regulatory cascade do not appear operational in this leukemia. Further, we identify a novel subgroup of patients with CLL with early progressive disease that appears particularly sensitive to MDM2 inhibitor treatment. These data provide definitive evidence for target-specific and predictive activity and a rationale to proceed with this potentially important class of compounds in the treatment of CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Shangary, D. Qin, D. McEachern, M. Liu, R. S. Miller, S. Qiu, Z. Nikolovska-Coleska, K. Ding, G. Wang, J. Chen, et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition PNAS, March 11, 2008; 105(10): 3933 - 3938. [Abstract] [Full Text] [PDF]

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