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Prepublished online as a Blood First Edition Paper on February 20, 2003; DOI 10.1182/blood-2002-10-3306. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-10-3306v1 101/12/4944    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 Wiestner, A. Articles by Staudt, L. M. Search for Related Content PubMed PubMed Citation Articles by Wiestner, A. Articles by Staudt, L. M. Related Collections Neoplasia Signal Transduction Gene Expression Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2003, Vol. 101, No. 12, pp. 4944-4951 NEOPLASIA ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile Adrian Wiestner, Andreas Rosenwald, Todd S. Barry, George Wright, R. Eric Davis, Sarah E. Henrickson, Hong Zhao, Rachel E. Ibbotson, Jenny A. Orchard, Zadie Davis, Maryalice Stetler-Stevenson, Mark Raffeld, Diane C. Arthur, Gerald E. Marti, Wyndham H. Wilson, Terry J. Hamblin, David G. Oscier, and Louis M. Staudt From the Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD; Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Hematology, Royal Bournemouth Hospital, United Kingdom; Office of Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD; Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD. The presence or absence of somatic mutations in the expressed immunoglobulin heavy chain variable regions (IgVH) of chronic lymphocytic leukemia (CLL) cells provides prognostic information. Patients whose leukemic cells express unmutated IgVH regions (Ig-unmutated CLL) often have progressive disease, whereas patients whose leukemic cells express mutated IgVH regions (Ig-mutated CLL) more often have an indolent disease. Given the difficulty in performing IgVH sequencing in a routine diagnostic laboratory, this prognostic distinction is currently unavailable to most patients. Pilot gene expression profiling studies in patients with CLL identified genes that were differentially expressed between the Ig-unmutated and Ig-mutated CLL subtypes. Here, we have profiled an expanded cohort of 107 patients and show that ZAP-70 is the gene that best distinguishes the CLL subtypes. Ig-unmutated CLL expressed ZAP-70 5.54-fold more highly than Ig-mutated CLL (P < 10-21). ZAP-70 expression correctly predicted IgVH mutation status in 93% of patients. ZAP-70 expression and IgVH mutation status were comparable in their ability to predict time to treatment requirement following diagnosis. In 7 patients, ZAP-70 expression and IgVH mutation status were discordant: 4 Ig-mutated CLLs had high ZAP-70 expression and 3 Ig-unmutated CLLs had low ZAP-70 expression. Among these ZAP-70 "outliers," those with Ig-mutated CLL had clinical features that are uncharacteristic of this CLL subtype: 2 required early treatment and 2 used a mutated VH3-21 gene, an IgVH gene that has been associated with progressive disease. We developed reverse transcriptase–polymerase chain reaction and immunohistochemical assays for ZAP-70 expression that can be applied clinically and would yield important prognostic information for patients with CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Kujawski, P. Ouillette, H. Erba, C. Saddler, A. Jakubowiak, M. Kaminski, K. Shedden, and S. N. 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