Immunohistochemical detection of ZAP70 in chronic lymphocytic leukemia predicts immunoglobulin heavy chain gene mutation status and time to progression

Joan Admirand, Ronald J. Knoblock, Kevin R. Coombes, Constantine Tam, Ellen J. Schlette, William G. Wierda, Alessandra Ferrajoli, Susan O'Brien, Michael J. Keating, Rajyalakshmi Luthra, L. Jeffrey Medeiros, Lynne V. Abruzzo

Research output: Contribution to journalArticle

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Abstract

Zeta-associated protein-70 (ZAP70) expression measured by flow cytometry has been proposed as a surrogate marker of the somatic mutation status of the immunoglobulin heavy chain variable region (IGHV) genes in chronic lymphocytic leukemia. However, attempts to implement this approach in clinical flow cytometry laboratories have been problematic; many commercially available antibodies give unreliable results. Assessment of ZAP70 protein expression by immunohistochemistry in chronic lymphocytic leukemia tissue sections is an easy, alternative approach, although lack of quantitation and subjective interpretation of results are potential pitfalls. In this study, we correlated ZAP70 protein expression, assessed by immunohistochemistry, with ZAP70 messenger RNA (mRNA) transcript expression, assessed by semi-quantitative real-time reverse transcriptase-polymerase chain reaction assay, with the somatic mutation status of the IGHV genes in previously untreated patients with chronic lymphocytic leukemia. Expression of ZAP70 protein and mRNA transcripts correlated strongly (P8.238 × 10-12). Expression of ZAP70 protein and mRNA transcripts also correlated strongly with the somatic mutation status of the IGHV genes (P=0.000071 and P0.00076, respectively). Further, ZAP70 positivity by immunohistochemistry was associated with an increased risk of progression to therapy requirement (3-year risk 83% vs 31% for ZAP70 negative by immunohistochemistry, P0.03). These results show that ZAP70 expression assessed by immunohistochemistry is a reliable surrogate marker of the somatic mutation status of the IGHV genes, and predicts time to progression.

Original languageEnglish (US)
Pages (from-to)1518-1523
Number of pages6
JournalModern Pathology
Volume23
Issue number11
DOIs
StatePublished - Nov 1 2010

Fingerprint

Immunoglobulin Heavy Chain Genes
B-Cell Chronic Lymphocytic Leukemia
Mutation
Proteins
Immunoglobulin Heavy Chains
Immunohistochemistry
Messenger RNA
Genes
Flow Cytometry
Biomarkers
Reverse Transcriptase Polymerase Chain Reaction

Keywords

  • QRT-PCR
  • ZAP70
  • chronic lymphocytic leukemia
  • immunoglobulin heavy chain variable region genes
  • immunohistochemistry
  • somatic mutation status

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Immunohistochemical detection of ZAP70 in chronic lymphocytic leukemia predicts immunoglobulin heavy chain gene mutation status and time to progression. / Admirand, Joan; Knoblock, Ronald J.; Coombes, Kevin R.; Tam, Constantine; Schlette, Ellen J.; Wierda, William G.; Ferrajoli, Alessandra; O'Brien, Susan; Keating, Michael J.; Luthra, Rajyalakshmi; Medeiros, L. Jeffrey; Abruzzo, Lynne V.

In: Modern Pathology, Vol. 23, No. 11, 01.11.2010, p. 1518-1523.

Research output: Contribution to journalArticle

Admirand, J, Knoblock, RJ, Coombes, KR, Tam, C, Schlette, EJ, Wierda, WG, Ferrajoli, A, O'Brien, S, Keating, MJ, Luthra, R, Medeiros, LJ & Abruzzo, LV 2010, 'Immunohistochemical detection of ZAP70 in chronic lymphocytic leukemia predicts immunoglobulin heavy chain gene mutation status and time to progression', Modern Pathology, vol. 23, no. 11, pp. 1518-1523. https://doi.org/10.1038/modpathol.2010.131
Admirand, Joan ; Knoblock, Ronald J. ; Coombes, Kevin R. ; Tam, Constantine ; Schlette, Ellen J. ; Wierda, William G. ; Ferrajoli, Alessandra ; O'Brien, Susan ; Keating, Michael J. ; Luthra, Rajyalakshmi ; Medeiros, L. Jeffrey ; Abruzzo, Lynne V. / Immunohistochemical detection of ZAP70 in chronic lymphocytic leukemia predicts immunoglobulin heavy chain gene mutation status and time to progression. In: Modern Pathology. 2010 ; Vol. 23, No. 11. pp. 1518-1523.
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