Zap-70, zeta-associated protein

ZAP-70 is a 70 kDa member of the Syk family of tyrosine kinases2,6. It is involved in T and NK cell receptor transduction11. It plays a role in the transition of pro-B to pre-B cells in the bone marrow, a checkpoint controlled by signals from the pre-B cell receptor (pre-BCR), which monitors for successful rearrangement of immunoglobulin heavy chain genes15.

Activated Hsp90 bound and stabilized ZAP-70: ZAP-70 expression in CLL cells confers markedly heightened sensitivity to 17-allyl-amino-demethoxy-geldanamycin or 17-dimethylaminoethylamino-17-demethoxygeldanamycin, suggesting that these or other Hsp90 inhibitors could be valuable therapeutically in patients with aggressive CLL5.

Immunohistochemical expression

ZAP-70 is expressed by many lymphoma types:



Precursor B-cell lymphoblastic lymphoma

5/61, 25%17



11/371 8/87, 50%17

Mantle cell lymphoma

5/391, 0/67

Burkitt lymphoma


Extranodal marginal zone lymphoma


Nodal marginal zone lymphoma


Splenic marginal zone lymphoma


Follicular lymphoma

0/211, 15%17



Lymphoplasmacytic lymphoma

0/101, 9%17


0/261, 27%17

Extranodal natural killer (NK) / T-cell lymphoma, nasal-type


Enteropathy-type T-cell lymphoma


Subcutaneous panniculitis-like T-cell lymphoma


Mycosis fungoides


Primary cutaneous CD30 positive T-cell lymphoproliferative disorder


Precursor T-lymphoblastic lymphoma


Peripheral T-cell lymphoma


Blastic NK-cell lymphoma


T-cell prolymphocytic leukemia


Anaplastic large cell lymphoma


Angioimmunoblastic T-cell lymphoma


T-cell lymphoma NOS


Hodgkin lymphoma



ZAP-70 staining in B-cell lymphomas and reactive T cells is predominantly nuclear with variable cytoplasmic staining. By contrast, ZAP-70 staining in T/NK-cell lymphomas is heterogeneous, with a shift from predominantly nuclear to predominantly cytoplasmic staining, particularly in those neoplasms with high-grade morphology1.


Diagnostic utility


1 Admirand JH, Rassidakis GZ, Abruzzo LV, et al. Immunohistochemical detection of ZAP-70 in 341 cases of non-Hodgkin and Hodgkin lymphoma. Mod Pathol 2004; 17:954-61

2 Bene MC What is ZAP-70? Cytometry B Clin Cytom 2006; 70:204-8

3 Best OG, Ibbotson RE, Parker AE, et al. ZAP-70 by flow cytometry: a comparison of different antibodies, anticoagulants, and methods of analysis. Cytometry B Clin Cytom 2006; 70:235-41

4 Carreras J, Villamor N, Colomo L, et al. Immunohistochemical analysis of ZAP-70 expression in B-cell lymphoid neoplasms. J Pathol 2005; 205:507-13

5 Castro JE, Prada CE, Loria O, et al. ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood 2005; 106:2506-12 FULL TEXT

6 Chan AC, Iwashima M, Turck CW, et al. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 1992; 71:649-62

7 Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348:1764-75 FULL TEXT

8 Del Principe MI, Del Poeta G, Buccisano F, et al. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood 2006; 108:853-61

9 Hui D, Dabbagh L, Hanson J, et al. High ZAP-70 expression correlates with worse clinical outcome in mantle cell lymphoma. Leukemia 2006; 20:1905-8

10 Huttmann A, Klein-Hitpass L, Thomale J, et al. Gene expression signatures separate B-cell chronic lymphocytic leukaemia prognostic subgroups defined by ZAP-70 and CD38 expression status. Leukemia 2006; 20:1774-82

11 Latour S,Veillette A. Proximal protein tyrosine kinases in immunoreceptor signaling. Curr Opin Immunol 2001; 13:299-306

12 Meyerson HJ, MacLennan G, Husel W, et al. D cyclins in CD5+ B-cell lymphoproliferative disorders: cyclin D1 and cyclin D2 identify diagnostic groups and cyclin D1 correlates with ZAP-70 expression in chronic lymphocytic leukemia. Am J Clin Pathol 2006; 125:241-50

13 Orchard J, Ibbotson R, Best G, et al. ZAP-70 in B cell malignancies. Leuk Lymphoma 2005; 46:1689-98

14 Orchard JA, Ibbotson RE, Davis Z, et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 2004; 363:105-11

15 Schweighoffer E, Vanes L, Mathiot A, et al. Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion. Immunity 2003; 18:523-33

16 Schade U, Bock O, Vornhusen S, et al. Bone marrow infiltration pattern in B-cell chronic lymphocytic leukemia is related to immunoglobulin heavy-chain variable region mutation status and expression of 70-kd zeta-associated protein (ZAP-70). Hum Pathol 2006; 37:1153-61

17 Wang J, Young L, Win W, et al. Distribution and ZAP-70 expression of WHO lymphoma categories in Shanxi, China: a review of 447 cases using a tissue microarray technique. Appl Immunohistochem Mol Morphol 2005; 13:323-32

18 Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003; 101:4944-51 FULL TEXT

19 Zanotti R, Ambrosetti A, Lestani M, et al. ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor. Leukemia 2006

This page last revised 12.11.2006.

©SMUHT/PW Bishop