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

In benign lymph nodes, nuclear ZAP-70 staining was seen in paracortical T lymphocytes and rare, scattered, small lymphocytes in the mantle zones and follicle centers. Histiocytes demonstrate coarse, granular cytoplasmic staining with ZAP-70. This staining may not be specific1.

ZAP-70 is expressed by many lymphoma types:

B-precursor lymphoblastic lymphoma
Expression correlates with immunoglobulin heavy-chain variable region gene mutational status in CLL/SLL4, and can be detected reliably using immunohistochemical methods7. The expression of ZAP-70 is commonly assessed by flow cytometry3, although this can be problematic13. Cyclin D1 levels are higher in ZAP-70-positive CLL cases12. In the bone marrow, diffuse infiltration is associated with ZAP-70 positivity and unmutated IgVH, a nodular pattern with negativity and mutated IgVH16.

	Precursor B-cell lymphoblastic lymphoma	5/61, 25%17
	CLL/SLL	11/371 8/8(all lacked IgH mutation)7, 50%17
	Mantle cell lymphoma	5/391, 0/67
	Burkitt lymphoma	1/121
	Extranodal marginal zone lymphoma	0/241
	Nodal marginal zone lymphoma	1/121
	Splenic marginal zone lymphoma	0/61
	Follicular lymphoma	0/211, 15%17
	Myeloma	0/101
	Lymphoplasmacytic lymphoma	0/101, 9%17
	DLBCL	0/261, 27%17
	Extranodal natural killer (NK) / T-cell lymphoma, nasal-type	6/61
	Enteropathy-type T-cell lymphoma	4/41
	Subcutaneous panniculitis-like T-cell lymphoma	4/51
	Mycosis fungoides	6/81
	Primary cutaneous CD30 positive T-cell lymphoproliferative disorder	7/121
	Precursor T-lymphoblastic lymphoma	3/51
	Peripheral T-cell lymphoma	10/171
	Blastic NK-cell lymphoma	2/41
	T-cell prolymphocytic leukemia	1/31
	Anaplastic large cell lymphoma	13/52(11/27 ALK-negative, 2/25 ALK-positive)1
	Angioimmunoblastic T-cell lymphoma	1/61
	T-cell lymphoma NOS	61%17
	Hodgkin lymphoma	0/161

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

Prognosis of CLL/SLL: positivity is associated with shorter survival4,7,13,14,18. Although ZAP-70 positivity19, CD38 positivity and unmutated IgV(H) are all associated with an inferior prognosis, ZAP-70 appears to be the superior predictor of outcome8. The positivity for ZAP-70 and CD38 is in turn associated with different expression of numerous other genes10.
Prognosis of mantle cell lymphoma is worse if ZAP-70 is positive9.