Zap-70 Associated with More Aggressive CLL

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Blood First Edition Paper

prepublished online August 8, 2002;

Submitted June 11, 2002

Accepted July 21, 2002

Expression of ZAP-70 is associated with increased

B-cell receptor signaling in chronic lymphocytic

leukemia

Liguang Chen, Widhopf, Lang Huynh,

Rassenti, Kanti R Rai, Arthur Weiss, and J

Kipps*

Department of Medicine, Division of

Hematology/Oncology, University of California-San

Diego School of Medicine, La Jolla, CA, USA; CLL

Research Consortium, San Diego, CA, USA

Department of Medicine, Long Island Jewish Hospital,

New Hyde Park, NY, USA; CLL Research Consortium, San

Diego, CA, USA

Medical Institute, Department of

Medicine, University of California, San Francisco, San

Francisco, CA, USA

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

We examined isolated leukemia B cells of patients with

chronic lymphocytic leukemia (CLL) for expression of

ZAP-70. CLL B cells that have non-mutated

immunoglobulin (Ig) variable region genes (V genes)

expressed levels of ZAP-70 protein that were

comparable to that expressed by normal blood T cells.

In contrast, CLL B cells that had mutated Ig V genes,

or that had low-level expression of CD38, generally

did not express detectable amounts of ZAP-70 protein.

Leukemia cells from identical twins with CLL were

found discordant for expression of ZAP-70, suggesting

that B-cell expression of ZAP-70 is not genetically

predetermined.

Ligation of the B cell receptor (BCR) complex on CLL

cells that expressed ZAP-70 induced significantly

greater tyrosine phosphorylation of cytosolic

proteins, including p72Syk, than did similar

stimulation of CLL cells that did not express ZAP-70.

Also, exceptional cases of CLL cells that expressed

mutated Ig V genes and ZAP-70 also experienced higher

levels tyrosine phosphorylation of such cytosolic

proteins following BCR-ligation.

Following BCR-ligation, ZAP-70 underwent tyrosine

phosphorylation and became associated with surface Ig

and CD79b, arguing that ZAP-70 is involved in

BCR-receptor signaling.

These data indicate that expression of ZAP-70 is

associated with enhanced signal transduction via the

BCR complex, which may contribute to the more

aggressive clinical course associated with CLL cells

that express non-mutated Ig receptors.

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