ZAP-70 Accurately Predicts IgVH Mutational Status

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Blood First Edition Paper

prepublished online February 20, 2003

Submitted November 4, 2002

Accepted February 2, 2003

ZAP-70 expression identifies a chronic lymphocytic leukemia subtype

with unmutated immunoglobulin genes, inferior clinical outcome, and

distinct gene expression profile

Wiestner, s Rosenwald, Todd S Barry, , R

, E Henrickson, Hong Zhao, E Ibbotson, A

Orchard, Zadie , alice Stetler-son, Mark Raffeld,

Diane C Arthur, Gerald E Marti, Wyndham H , Terry J Hamblin,

G Oscier, and Louis M Staudt*

Metabolism Branch, Center for Cancer Research, National Cancer

Institute, National Institutes of Health, Bethesda, MD, USA

Hematology Branch, National Heart, Lung and Blood Institute, National

Institutes of Health, Bethesda, MD, USA

Laboratory of Pathology, National Cancer Institute, National

Institutes of Health, Bethesda, MD, USA

Biometric Research Branch, Division of Cancer Treatment and

Diagnosis, National Cancer Institute, National Institutes of Health,

Bethesda, MD, USA

Department of Hematology, Royal Bournemouth Hospital, Bournemouth,

United Kingdom

Office of Cellular, Tissue and Gene Therapies, Center for Biologics

Evaluation and Research, Food and Drug Administration, Bethesda, MD,

USA

Medicine Branch, Division of Clinical Sciences, National Cancer

Institute, National Institutes of Health, Bethesda, MD, USA

* Corresponding author; email: lstaudt@....

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 CLL patients 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 shown

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 RT-PCR and immunohistochemical assays for ZAP-70

expression that can be applied clinically and would yield important

prognostic information for CLL patients.

http://www.bloodjournal.org/cgi/content/abstract/2002-10-3306v1