A pathobiological role of the insulin receptor in chronic lymphocytic leukemia.

PURPOSE

The chromosomal deletion 11q affects biology and clinical outcome in chronic lymphocytic leukemia (CLL) but del11q-deregulated genes remain incompletely characterized.

EXPERIMENTAL DESIGN

We have employed integrated genomic profiling approaches on CLL cases with and without del11q to identify 11q-relevant genes.

RESULTS

We have identified differential expression of the insulin receptor (INSR) in CLL, including high-level INSR expression in the majority of CLL with del11q. High INSR mRNA expression in 11q CLL (∼10-fold higher mean levels than other genomic categories) was confirmed by quantitative PCR in 247 CLL cases. INSR protein measurements in 257 CLL cases through flow cytometry, compared with measurements in normal CD19(+) B cells and monocytes, confirmed that a subset of CLL aberrantly expresses high INSR levels. INSR stimulation by insulin in CLL cells ex vivo resulted in the activation of canonical INSR signaling pathways, including the AKT-mTOR and Ras/Raf/Erk pathways, and INSR activation partially abrogated spontaneous CLL cell apoptosis ex vivo. Higher INSR levels correlated with shorter time to first therapy and shorter overall survival (OS). In bivariate analysis, INSR expression predicted for rapid initial disease progression and shorter OS in ZAP-70-low/negative CLL. Finally, in multivariate analysis (ZAP-70 status, IgV(H) status, and INSR expression), we detected elevated HRs and trends for short OS for CLL cases with high INSR expression (analyzed inclusive or exclusive of cases with del11q).

CONCLUSIONS

Our aggregate biochemical and clinical outcome data suggest biologically meaningful elevated INSR expression in a substantial subset of all CLL cases, including many cases with del11q.