ZAP-70 expression and proliferative activity in chronic lymphocytic leukemia

Abstract

The expression of 70 kDa protein zeta-associated protein (ZAP-70) in chronic lymphocytic leukemia (CLL) has been used to detect those patients with more aggressive disease. The aim of this study was to determine the proliferative activity of ZAP-70(+) leukemic cells by immunocytochemical methods. The study was undertaken on native blood marrow (BM) and peripheral blood (PB) smears from 65 patients with CLL. ZAP-70 was expressed in leukemic cells of 35 patients (54%). We demonstrated that ZAP-70 immunoreactivity correlated with Rai 0-IV (p = 0.002) and Binet A-C stages (p < 0.001), total tumor mass (TTM score) (p < 0.001), β2-microglobulin (p = 0.006), atypical lymphocytes (p < 0.001) and proliferative activity in bone marrow and peripheral blood (p = 0.014, p = 0.002, respectively) using χ(2) test and Mann-Whitney test. ZAP-70 protein expression is in direct correlation with the poorer prognostic parameters, which additionally confirms the successful method of detection of ZAP-70 expression. Higher Ki-67 expression in BM and PB smears of patients with ZAP-70(+) disease indicates higher proliferating compartments, which may contribute to poorer prognosis.

Co-culture of primary CLL cells with bone marrow mesenchymal cells, CD40 ligand and CpG ODN promotes proliferation of chemoresistant CLL cells phenotypically comparable to those proliferatingin vivo

“…Among the diverse molecular pathways of crosstalk between CLL cells and their microenvironment, BCR signaling has been recognized as one of the most important [ 17 ][ 18 ]. The expression of the protein tyrosine kinase ZAP-70 has been associated with increased BCR signaling in CLL [ 19 ] which translated into increased proliferation and migrative capacity of ZAP-70 positive subclones, based on in vitro and in vivo data [ 20 ],[ 21 ],[ 22 ],[ 23 ]. Clinically, ZAP-70 expression has been correlated with IgVH mutational status, disease progression and survival[ 24 ].…”

“…Additionally, the co-culture also resulted in stimulation of T cells from patients with CLL, which probably contributed to the activation of CLL cells. Besides its prognostic value, ZAP-70 expression is linked to activation of CLL cells[ 19 ],[ 22 ],[ 42 ] and its expression correlates with that of Ki-67 in CLL patients[ 21 ]. ZAP-70 expression has been clinically and biologically linked to aggressive features in CLL, but its regulation is still largely unknown; interestingly, we showed that the proliferative fraction of CLL cells from the PB was markedly enriched in ZAP-70 positive cells, and that the herein described co-culture system induced the expression of ZAP-70 in proliferating cells.…”

The Ubiquitin-Associated and SH3 Domain-Containing Proteins (UBASH3) Family in Mammalian Development and Immune Response

“…UBASH3B negatively regulates T-cell receptor (TCR) signalling in activated T-lymphocytes [25]. Additionally, it was shown that in vitro and in vivo, UBASH3B has an important protein tyrosine phosphatase activity that suppresses T-cell receptor signalling via the dephosphorylation of ZAP-70 [26] and Syk [27]. UBASH3B has been found to be a novel prognostic biomarker correlated with immune infiltrates in prostate cancer [25].…”