Additionally, ZAP-70 expression in CLL cells confers markedly heightened sensitivity to 17-AAG or 17-DMAG, suggesting that these or other Hsp90 inhibitors could be valuable therapeutically in patients with aggressive CLL.
Although it is premature to recommend therapy based on these risk factors, patients with ZAP-70-positive CLL cells should be monitored closely for disease progression as they have a median time from diagnosis to requiring initial therapy by standard criteria of approximately 3 years.
In 7 patients, ZAP-70 expression and IgVH mutation status were discordant: 4 Ig-mutated CLLs had high ZAP-70 expression and 3 Ig-unmutated CLLs had low ZAP-70 expression.
In particular, ZAP-70 is especially attractive because its aberrant expression in tumour cells from the more aggressive forms of CLL requires the chaperoning action of activated heat-shock protein 90, which may be specifically inhibited.
Measuring ZAP-70 methylation status at C-334 is a simple and reproducible method for predicting prognosis in CLL, which is closely associated with ZAP-70 expression and IgVH gene mutational status.
Some new prognostic factors, such as immunoglobulin variable heavy chain (IgVH) mutational status, zeta-associated protein (ZAP-70) and CD38 expression in leukemic cells were introduced to identify attenuated versus progressive types of CLL bearing the potential to facilitate risk-adapted treatment strategies.
These data point to the need for a more extensive study to evaluate the significance of Zap-70 and CD38 expression as indicators of IgVH mutation status and prognosis of CLL patients.
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.