Paolo Ghia, M.D., Ph.D. Instituto Scientifico San Raffaele (Italy)

GENETICS

Dissecting CLL heterogeneity by proteomic analysis

Grant awarded in 2005

Abstract:

CLL researchers are working to define which patients should be treated, when and how. It is important to look at the molecular differences of CLL which translates into remarkable clinical differences. The presence of somatic mutations in the immunoglobulin variable region (IGHV) genes and the expression of CD38 and ZAP-70 are examples that link biology to prognosis. We have used a proteomic approach to establish the protein expression profile of CLL cells from different subsets of patients.

We focused on the proteins involved in the transduction of signals delivered by the stimulation of surface antigen receptors, as these proteins might be responsible for a more persistent cell proliferation and/or prevention of apoptosis. We have discovered that a discriminating molecule is hematopoietic-lineage-cell-specific protein 1 (HS1), a protein pivotal in the signal cascade triggered by the B-cell-receptor stimulation. In 40 CLL cases we found that patients with aggressive disease expressed most HS1 protein in the phosphorylated form, while patients with stable disease had most HS1 in the unphosphorylated form. These observations have led us to ask three questions: 1) Can HS1 be used to build an integrated prognostic card for individual CLL patients? 2) Can HS1 be targeted for therapeutic purposes? 3) Can we detect other proteins that might become selective therapeutic targets?

To answer these questions we have devised the following experimental plan:
1) The prognostic significance of phosphorylated HS1 and its relationship with other prognostic markers will be evaluated in a large cohort of patients
2) The possibility of therapeutically targeting the phosphorylated form of HS1 will be investigated to provide the basis for designing specific inhibitors.
3) As preliminary data show that other proteins are differentially expressed in different CLL subsets, their expression pattern and functional role will be studied.