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.


RESULTS
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-.8).


CONCLUSIONS
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.
Orchard
Jenny A
JA
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
Ibbotson
Rachel E
RE
Davis
Zadie
Z
Wiestner
Adrian
A
Rosenwald
Andreas
A
Thomas
Peter W
PW
Hamblin
Terry J
TJ
Staudt
Louis M
LM
Oscier
David G
DG
D000368:Aged; D014408:Biomarkers, Tumor; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D051746:ZAP-70 Protein-Tyrosine Kinase
D014408:Biomarkers, Tumor; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human