ZAP-70 May Enhance CLL Signaling

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http://www.bloodjournal.org/cgi/content/full/105/5/1839

Blood, 1 March 2005, Vol. 105, No. 5, pp. 1839-1840.

Comment on Chen et al, page 2036

More ZAP for chronic lymphocytic leukemia (CLL)

Wiestner

NATIONAL HEART, LUNG AND BLOOD INSTITUTE

Antigen stimulation of the leukemic clone is increasingly implicated

in the pathogenesis of CLL. Chen and colleagues provide evidence that

expression of ZAP-70 in CLL B cells renders IgM signaling more

effective and thereby could contribute to the more rapidly

progressive clinical course of ZAP-70–positive CLL.

There is increasing evidence for a role of antigen in the

pathogenesis of chronic lymphocytic leukemia (CLL), most notably the

nonrandom composition of the B-cell receptor (BCR) expressed on the

leukemic cells, suggesting that CLL B cells recognize distinct

antigens.1 Ongoing antigen-mediated activation of the leukemic cells

through the B-cell receptor is suggested by the presence of cellular

activation markers on the cell surface and the expression of genes

induced by BCR stimulation in at least some CLL types.2,3 Other

features such as the low expression of the immunoglobulin chains on

the cell surface and reduced responsiveness to immunoglobulin M (IgM)

stimulation in some CLL clones are consistent with an anergic state

induced by chronic antigen exposure.1 Importantly, the nature of the

cognate antigen and differences in the responsiveness of the leukemic

cells to antigen stimulation may explain the well-known heterogeneity

in the clinical course of CLL.

Zeta-associated protein of 70 kDa (ZAP-70), a cytoplasmic tyrosine

kinase essential for T-cell–receptor signal transduction, is

preferentially expressed in CLL B cells whose immunoglobulin genes

have not undergone somatic hypermutation (Ig-unmutated CLL), while a

second CLL subtype with mutated immunoglobulin genes most often lacks

ZAP-70 expression.3 Expression of ZAP-70 in CLL B cells is associated

with more rapid disease progression and shorter survival4 and may be

a better predictor of clinical course than Ig-mutation status.5

Whether ZAP-70 expression indicates a distinct cellular origin of the

clone or different activation states of the leukemic cells remains to

be determined. Chen and colleagues focused on a role of ZAP-70 in BCR

signal transduction and demonstrate that CLL B cells that express ZAP-

70 are more likely to respond to IgM cross-linking with increased

tyrosine phosphorylation of key signal transduction proteins and

increased calcium flux than ZAP-70–negative CLL B cells.

By introducing ZAP-70 into ZAP-70–negative CLL cells, they could

convert IgM-nonresponsive B cells to IgM-responsive cells. While this

finding supports a direct role of ZAP-70 in IgM signaling, it is not

evident how expression of ZAP-70 increases BCR signaling in CLL B

cells, as these cells do express normal amounts of SYK kinase, the

functional B-cell homolog of ZAP-70. It is conceivable, however, that

ZAP-70 expression may antagonize mechanisms involved in

downmodulating BCR activity in anergic B cells and thereby could

facilitate BCR signaling.

The evidence implicating ZAP-70 in BCR signaling is derived from in

vitro experiments using a controlled but artificial way to initiate

IgM signaling. It is therefore important to test predictions of this

model in vivo and to keep in mind that ZAP-70 expression

distinguishes 2 CLL subtypes that differ in several respects, not the

least of which may be the nature of the antigen recognized and

possible differences in the interaction with nonmalignant cells and

in BCR composition. All of these factors may influence the

consequences of BCR engagement in vivo that can range from increased

proliferation and survival to induction of apoptosis.

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Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene

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Orchard JA, Ibbotson RE, Z, et al. ZAP-70 expression and

prognosis in chronic lymphocytic leukaemia. Lancet. 2004;363: 105-111.

[CrossRef][Medline] [Order article via Infotrieve]

Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with

immunoglobulin heavy-chain gene mutation status as a predictor of

disease progression in chronic lymphocytic leukemia. N Engl J Med.

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Related Article in Blood Online:

ZAP-70 directly enhances IgM signaling in chronic lymphocytic

leukemia

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

McGahan, Rassenti, Arthur Weiss, and J. Kipps

Blood 2005 105: 2036-2041. [Abstract] [Full Text]