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ZAP-70 expression and prognosis in chronic lymphocytic leukaemia

ZAP-70 expression and prognosis in chronic lymphocytic leukaemia
ZAP-70 expression and prognosis in chronic lymphocytic leukaemia
Background: Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease; many patients never need treatment, whereas some have poor outcomes. New treatments, which can induce complete remissions, allow patients with poor outlook to be treated while they are still asymptomatic. Whether or not the IgVH gene is mutated is the best predictor of clinical outcome, but this assay is unsuited to the routine laboratory. The gene coding for ZAP-70, a tyrosine kinase protein normally expressed in T and NK cells, has been shown by gene-expression profiling to be differentially expressed between patients with mutated and unmutated IgVH genes. We assessed whether ZAP-70 could be used as a prognostic marker in CLL.
Methods: We developed a flow cytometry assay for ZAP-70 protein expression and investigated its concordance with ZAP-70 mRNA expression, IgVH gene mutational status, and clinical outcome in 167 patients with CLL.
Findings: We showed high concordance between ZAP-70 protein expression and IgVH gene mutations. 108 patients (65%) had mutated IgVH genes and were ZAP-70 negative; 46 (28%) had unmutated IgVH genes and were ZAP-70 positive. Findings were discordant in 13 patients: six (4%) had mutated IgVH genes but were ZAP-70 positive, and seven (4%) had unmutated IgVH genes and were ZAP-70 negative. Expression of mRNA showed 97% concordance with ZAP-70 protein. Median survival was 24·4 years (95% CI 15·1–33·8) in ZAP-70 negative patients and 9·3 years (7·0–11·5) in those who were ZAP-70 positive (hazard ratio 5·5, 2·8–10·8).
Interpretation: ZAP-70 protein, which can be measured by flow cytometry in the general laboratory, is a reliable prognostic marker in CLL, equivalent to that of IgVH gene mutational status.
105-111
Orchard, J.A.
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Ibbotson, R.E.
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Davis, Z.
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Wiestner, A.
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Rosenwald, A.
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Thomas, P.W.
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Hamblin, T.J.
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Staudt, L.M.
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Oscier, D.G.
c2620a1d-25bb-48f7-9651-f5d023636381
Orchard, J.A.
534ac42d-aef9-4323-a7a4-130f6c514ccc
Ibbotson, R.E.
300e87bd-1bf5-4be3-9b36-bd5844ed457f
Davis, Z.
b106965c-11bb-4133-98f0-540894dd11a9
Wiestner, A.
2c32a6ce-f401-4bdf-9d56-290cccb0012c
Rosenwald, A.
374320dc-80c2-43c3-953f-3fdb1584789e
Thomas, P.W.
7fb3690c-c304-4a3b-864e-bd2415f3db16
Hamblin, T.J.
85c9639a-7cf1-4477-9267-e6d772ba66ab
Staudt, L.M.
59b3a8fc-c5c3-45ca-b57c-1cc144b6d86f
Oscier, D.G.
c2620a1d-25bb-48f7-9651-f5d023636381

Orchard, J.A., Ibbotson, R.E., Davis, Z., Wiestner, A., Rosenwald, A., Thomas, P.W., Hamblin, T.J., Staudt, L.M. and Oscier, D.G. (2004) ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. The Lancet, 363 (9403), 105-111. (doi:10.1016/S0140-6736(03)15260-9).

Record type: Article

Abstract

Background: Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease; many patients never need treatment, whereas some have poor outcomes. New treatments, which can induce complete remissions, allow patients with poor outlook to be treated while they are still asymptomatic. Whether or not the IgVH gene is mutated is the best predictor of clinical outcome, but this assay is unsuited to the routine laboratory. The gene coding for ZAP-70, a tyrosine kinase protein normally expressed in T and NK cells, has been shown by gene-expression profiling to be differentially expressed between patients with mutated and unmutated IgVH genes. We assessed whether ZAP-70 could be used as a prognostic marker in CLL.
Methods: We developed a flow cytometry assay for ZAP-70 protein expression and investigated its concordance with ZAP-70 mRNA expression, IgVH gene mutational status, and clinical outcome in 167 patients with CLL.
Findings: We showed high concordance between ZAP-70 protein expression and IgVH gene mutations. 108 patients (65%) had mutated IgVH genes and were ZAP-70 negative; 46 (28%) had unmutated IgVH genes and were ZAP-70 positive. Findings were discordant in 13 patients: six (4%) had mutated IgVH genes but were ZAP-70 positive, and seven (4%) had unmutated IgVH genes and were ZAP-70 negative. Expression of mRNA showed 97% concordance with ZAP-70 protein. Median survival was 24·4 years (95% CI 15·1–33·8) in ZAP-70 negative patients and 9·3 years (7·0–11·5) in those who were ZAP-70 positive (hazard ratio 5·5, 2·8–10·8).
Interpretation: ZAP-70 protein, which can be measured by flow cytometry in the general laboratory, is a reliable prognostic marker in CLL, equivalent to that of IgVH gene mutational status.

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Published date: 2004
Organisations: Cancer Sciences

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Local EPrints ID: 26503
URI: http://eprints.soton.ac.uk/id/eprint/26503
PURE UUID: 6b8333a8-7ad1-4e60-beb9-6a2b85068341

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Date deposited: 21 Apr 2006
Last modified: 15 Aug 2024 17:11

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Contributors

Author: J.A. Orchard
Author: R.E. Ibbotson
Author: Z. Davis
Author: A. Wiestner
Author: A. Rosenwald
Author: P.W. Thomas
Author: T.J. Hamblin
Author: L.M. Staudt
Author: D.G. Oscier

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