A PATHOBIOLOGICAL ROLE OF THE INSULIN RECEPTOR IN CHRONIC LYMPHOCYTIC LEUKEMIA

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BlankA PATHOBIOLOGICAL ROLE OF THE INSULIN RECEPTOR IN CHRONIC LYMPHOCYTIC

LEUKEMIA

1.. Kamlai Saiya-Cork1,

2.. Roxane 1,

3.. Parkin1,

4.. Ouillette1,

5.. Erlene Kuizon1,

6.. Kujawski2,

7.. Harry Erna1,

8.. a Campagnaro3,

9.. Kerby Shedden4,

10.. Mark Kaminski1, and

11.. Sami N. Malek5,*

+ Author Affiliations

1.. 1Internal Medicine, University of Michigan

2.. 2

3.. 3Internal Medicine, Case Western Hospitals and Clinics

4.. 4Dept. of Biostatistics, University of Michigan

5.. 5Med-Hematology/ Oncology, University of Michigan

1.. * Corresponding Author:

Sami N. Malek, Med-Hematology/ Oncology, University of Michigan, 1500 E

Medical Center Drive, 4312 Cancer Center, Ann Arbor, MI, 48109, United States

smalek@...

Abstract

Purpose: The chromosomal deletion 11q affects biology and clinical outcome in

CLL but del11q-deregulated genes remain incompletely characterized. Experimental

Design: We have employed integrated genomic profiling approaches upon 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 Q-PCR in 247 CLL cases. INSR protein measurements

in 257 CLL cases through FACS, 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 (TTFT) 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, IgVH

status and INSR expression), we detected elevated hazard ratios 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.

a.. Received August 2, 2010.

b.. Revision received January 6, 2011.

c.. Accepted January 21, 2011.