A Pathobiological Role of the Insulin Receptor in Chronic Lymphocytic Leukemia.

Abstract 2324

Poster Board II-301

The presence of genomic aberrations in CLL, including del17p and del11q, affects CLL patient survival, and thus an in-depth understanding of the genes influenced through these deletions is important. Further, genes affecting CLL disease progression that is observed in patients with recurrent genomic deletions, including del11q, remain incompletely characterized. Focusing therefore on del11q in CLL, we employed comparative expression array profiling (Affymetrix 133 2.0 plus arrays) of RNA from sorted CD19+ cells from 10 cases with and nine cases without del11q to identify stable transcriptome differences associated with del11q. Through these efforts we have identified for the first time differential expression of the insulin receptor (INSR) in CLL and predominant INSR expression in CLL with del11q. We have validated this finding in a cohort of 219 CLL cases. Our aggregate data suggest biologically and clinically meaningful INSR expression in a substantial subset of all CLL cases. INSR stimulation by insulin in CLL cells expressing the INSR resulted in the activation of canonical INSR signaling pathways, including the AKT-mTOR and Ras/Raf/Erk pathways, and INSR activation partially abrogated CLL cell apoptosis ex vivo. Clinically, CLL cases with INSR expression displayed larger lymphnodes and higher Rai stage at study enrollment and the disease progressed faster requiring repeat therapy earlier than CLL cases with low or absent INSR expression. This novel data provides the first description of a pathobiological role of the insulin receptor in CLL biology and disease progression, thus identifying a potential mediator and mechanism for del11q-associated CLL phenotypes. The identification of a transmembrane tyrosine kinase receptor with direct effects on CLL biology and clinical behavior offers opportunities for CLL prognostication and targeted therapy development and further strengthens the case for involvement of the INSR in cancer biology.