ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor

Abstract

Zeta-associated protein-70 (ZAP-70), mostly assessed by flowcytometry (FC), recently emerged as reliable prognostic factor in chronic lymphocytic leukaemia (CLL) at presentation. We evaluated ZAP-70 expression in 156 CLL patients by immunohistochemistry (IHC) on formalin-fixed bone marrow (BM) biopsies at diagnosis. At presentation, 117 patients (75%) were with Binet stage A, 27 (17%) stage B and 12 (8%) stage C. Median follow-up was 61 months (range 6-242). ZAP-70 was expressed in neoplastic lymphocytes of 69 patients (44%). Concordance between ZAP-70 by IHC and ZAP-70 by FC, immunoglobulin heavy chain variable genes (IGHV) mutational status and CD38 expression was found in 41/46 (89%), 41/49 (80%) and in 60/88 (68%) tested cases, respectively. ZAP-70 expression significantly correlated with advanced Binet stage (B-C), diffuse BM infiltration, increased lactate dehydrogenase (LDH) and b2-microglobulin serum levels and lymphocyte doubling time o12 months. ZAP-70 positivity was significantly related to poorer time to progression (median 16 months vs 158 of ZAP-70-negative cases) (Po0.0001) and overall survival (median 106 months vs not reached) (P ¼ 0.0002); this correlation was confirmed at multivariate analysis. ZAP-70 expression correlated with poorer outcome also when evaluated only in the 117 stage A patients. In conclusion, immunohistological detection of ZAP-70 on formalin-fixed BM biopsies at diagnosis appears a useful methodological approach to identify patients with poor prognosis in CLL.

Quantification of ZAP70 mRNA in B Cells by Real-Time PCR Is a Powerful Prognostic Factor in Chronic Lymphocytic Leukemia

“…In contrast, we found the difference in OS survival times for ZAP70 expression to be highly significant (P ϭ 0.0021). The median OS time for ZAP70 ϩ patients was 12.7 years, which is similar to previously reported findings (14,16,18 ). Only 3 studies have demonstrated a correlation between ZAP70 expression and OS; the other studies evaluated ZAP70's prognostic value only in terms of TFS.…”

“…Patients with Ͻ20% ZAP70 ϩ B cells as measured by flow cytometry (FC) generally had a mutated IGHV status, and patients with Ն20% ZAP70 ϩ cells had an unmutated IGHV status. Further clinical studies confirmed the prognostic value of the ZAP70 protein (14)(15)(16)(17)(18)(19)(20); however, FC measurement of ZAP70 status is often inaccurate at the positivity limit (21 ) because of low resolution of the positive and negative populations, and can also be influenced by the gating procedure and antibody choice (22 ). To offset these drawbacks, investigators have proposed absolute quantification of ZAP70 mRNA (23,24 ).…”

Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells

“…Therefore, we compared Hh member expression within prognostically relevant risk groups on the basis of Rai staging (Rai et al, 1975), immunoglobulin heavy chain variable gene mutational status, CD38 expression (Damle et al, 1999) and cytogenetic abnormalities (Dohner et al, 2000;Wiestner et al, 2003;Zanotti et al, 2007). We detected significantly higher SMOH expression in groups with unfavorable cytogenetic abnormalities compared with normal karyotypes (P ¼ 0.035), as increased SMOH expression was observed in patients with trisomy 12 (Tri12; Figure 2a).…”

Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro

“…18 In this study, the expression of thioredoxin was not related to the mutated or unmutated status of IGHV genes. However, because few mutated cases were included, this may only imply that the potential leukemia growthpromoting effect mediated by thioredoxin is independent of the IGHV mutational status of the CLL patient.…”