Recently, a new pathogenetic model involving miRNAs and protein coding genes (such as TP53 and ZAP-70) has been identified and explains the prognostic implications of the most recurrent chromosomal abnormalities in human B-cell chronic lymphocytic leukemia.
B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, occurs in two forms, aggressive (showing for the most part high ZAP-70 expression and unmutated IgH V(H)) and indolent (showing low ZAP-70 expression and mutated IgH V(H)).
In recent decades, numerous prognostic markers, such as immunoglobulin variable region heavy-chain (IgVH) mutational status, ZAP-70 and the expression of CD38 on leukaemic cells were introduced to screen for patients likely to have progressive course of B-CLL bearing the potential to facilitate risk-adapted treatment strategies.
ZAP-70 was significantly expressed in 28%, 54% and 61% of patients with Binet stages A, B and C B-cell chronic lymphocytic leukemia, respectively (p=0.008).
DNA microarrays have led to the discovery of better prognostic tools, including the use of Zap-70 in B-Cell Chronic Lymphocytic Leukemia (B-CLL) as an indicator of worse prognosis.
We investigated hTERT gene expression in 134 B-cell chronic lymphocytic leukemia (B-CLL) cases and evaluated its prognostic value with other prognostic markers (IgVH mutation status, CD38 and ZAP-70 expression).
To evaluate the relationship between ZAP-70 expression, mutation status, and the infiltration pattern in B-CLL, we analyzed bone marrow trephine biopsies from B-CLL patients (n = 35).
Additionally different reagents for permeabilization such as IntraPrep, FIX & PERM, Perm/Wash and 70% ethanol/paraformaldehyde were used to find the most clinically relevant and easy assay to determine ZAP-70 expression in B-CLL.
B-cell chronic lymphocytic leukaemia (B-CLL) is a heterogenous disease with a highly variable clinical course and analysis of zeta-associated protein 70 (ZAP-70) and CD38 expression on B-CLL cells allowed for identification of patients with good (ZAP-70-CD38-) and poor (ZAP-70+CD38+) prognosis.
Moreover, discordant ISO(+)TNK(-) cases had a IgV(H) gene mutation profile similar to that of concordantly positive cases and different from ZAP-70 concordantly negative B-CLL.
As opposed to groups II-III, group I B-CLLs lacked expression of ZAP-70 and activation-induced cytidine deaminase in the majority of cases, while more frequently had mutated IgV(H) genes and IgV(H) mutations consistent with antigen-driven selection.
Over-representation of high-risk genomic aberrations such as 17p deletion or 11q deletion and distribution of the IgV(H) mutation status in B-CLL discordant for ZAP-70/CD38 pointed toward a distinct biologic background of the observed disease subgroups.
With the addition of rituximab to fludarabine, improved clinical outcomes were obtained, and the stratification of patients by using ZAP-70 and CD38 may help clinicians offer more aggressive and/or experimental approaches to the treatment of patients with high-risk B-CLL subtypes.
These data show the characterization and generation of a novel murine leukemia model with many similarities to human ZAP-70+ B cell chronic lymphocytic leukemia.