Cyclin E but not bcl-2, bax or mcl-1 is differentially expressed in ZAP 70-positive and ZAP 70-negative B-CLL cells

Abstract

The clinical course of chronic lymphocytic leukemia is variable. While some patients have indolent disease, others require aggressive treatment within a short time after diagnosis. Differences in the expression of proteins regulating cell cycle and apoptosis may be responsible for the heterogeneous course of the disease. Recently, protein ZAP 70 [zeta-chain (T-cell receptor) associated protein kinase 70 kDa] has been found to be differentially expressed within two biologic subgroups, characterized by the presence or absence of somatic mutations in specific immunoglobulin heavy-chain variable region genes. In the present work, we analyzed highly purified B-CLL cells from 60 patients for ZAP 70 expression and the expression of cyclin E, bcl-2, bax, and mcl-1 as well as the ratios of bcl-2/bax and mcl-1/bax. The results indicate that cyclin E is expressed significantly higher in ZAP 70-positive as in ZAP 70-negative samples. We did not observe significant differences within the expression of Bcl-2 family member proteins. We conclude that higher cyclin E expression in samples of ZAP 70-positive patients may reflect a larger proliferating compartment in vivo compared to ZAP 70-negative patients and that cyclin E may add prognostic information in this context for patients with B-CLL.

Spontaneous apoptosis and proliferation detected by BCL-2 and CD71 proteins are important progression indicators within ZAP-70 negative chronic lymphocytic leukemia

“…Moreover, we found that bcl2-CD71-subset was significantly correlated with lower ZAP-70 (p ¼ 0.001), thus hypothesizing a reduced proliferation and higher apoptosis within ZAP-70 negative CLL subset. On this line, Bogner et al [46] observed a higher cyclin E expression in samples of ZAP-70 positive patients, which may reflect a larger proliferating compartment in vivo compared to ZAP 70 negative patients. In our opinion, high CD71 expression may represent both increased cell proliferation and cellular activation in CLL.…”

MiR-15a and miR-16-1 cluster functions in human leukemia

“…Despite the fact that MCL-1 expression is not different in ZAP 70-positive (aggressive) vs. ZAP 70-negative (indolent) B-CLL cells (37), it represents a relevant therapeutic target in both acute and chronic lymphoid malignancies, because its silencing is sufficient to promote apoptosis in ALL and CLL cells and increase sensitivity to rituximab-mediated apoptosis (38). Interestingly, miR-29b has also been identified to target Mcl1 in a cholangiocarcinoma model (39), and many pieces of evidence converge in defining a role of the miR-29 family as TSGs in both solid (40) and hematologic malignancies (41).…”

A pilot trial of the mTOR (mammalian target of rapamycin) inhibitor RAD001 in patients with advanced B-CLL

“…As expected, no difference was observed before and after treatment with more than 98% of cells in the G0 phase of the cell cycle in every sample tested (data not shown). We have reported previously that cyclin E is strongly expressed in B-CLL cells and is downregulated upon mTOR inhibition [7,20,22]. In addition, the cell cycle inhibitor p27 is also strongly expressed in B-CLL cells and is also regulated in part by mTOR [23,24].…”

“…Mabs specific for p27 (clone G173-524) were purchased from Pharmingen (San Diego, CA, USA). Analysis of ZAP-70 expression was performed with appropriate positive and negative controls as published previously [20] using a ZAP-70 antibody (clone 29) from BD Transduction Laboratory, Mississauga, Canada.…”