ZAP-70 Directly Enhances IgM Signaling in CLL; May Contribute to Prognosis

[Guest guest]

[several papers have been published on this aspect of unmutated CLL

in the past couple of years.

For example, see:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

cmd=Retrieve & db=PubMed & list_uids=12393552 & dopt=Abstract

and:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=12454750

and:

http://www.bloodjournal.org/cgi/content/abstract/103/12/4389 ]

Blood First Edition Paper, prepublished online October 28, 2004

Submitted May 5, 2004

Accepted October 22, 2004

ZAP-70 directly enhances IgM signaling in chronic lymphocytic

leukemia

Liguang Chen, Apgar, Lang Huynh, Dicker, Giago-

McGahan, Rassenti, Arthur Weiss, and J Kipps*

Division of Hematology/Oncology, Department of Medicine, University

of California, San Diego, CA, USA

Department of Cell Signaling Research, BD PharMingen, San Diego, CA,

USA

Department of Medicine, Medical Institute, University

of California San Francisco and the CLL Research Consortioum, San

Francisco, CA, USA

Chronic lymphocytic leukemia (CLL) B cells that express unmutated

immunoglobulin heavy-chain variable region genes (IgVH) generally

express ZAP-70, in contrast to normal B cells or most CLL cases with

mutated IgVH.

Following IgM-ligation*, ZAP-70+ CLL cells had significantly higher

levels of phosphorylated p72Syk, BLNK, and phospholipase-C (PLC), and

had greater [Ca2+]i flux, than did ZAP-70-negative CLL cases,

including unusual ZAP-70-negative cases with unmutated IgVH.

IgM-ligation of ZAP-70-negative CLL B cells infected with an

adenovirus vector encoding ZAP-70 induced significantly greater

levels of phosphorylated p72Syk, BLNK, and PLC, and had greater [Ca2+]

i flux than did similarly-stimulated, non-infected CLL cells or CLL

cells infected with a control adenovirus vector.

We conclude that expression of ZAP-70 in CLL allows for more

effective IgM-signaling in CLL B cells, a feature that could

contribute to the relatively aggressive clinical behavior generally

associated with CLL cells that express unmutated IgVH.

* A process of attaching/binding