title: A pathobiological role of the insulin receptor in chronic lymphocytic leukemia.
abstract: OBJECTIVE
  The chromosomal deletion 11q affects biology and clinical outcome in chronic lymphocytic leukemia (CLL) but del11q-deregulated genes remain incompletely characterized.
  
  
  METHODS
  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.
authors.affiliation: Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan 48109-0936, USA.
authors.forename: Kamlai
authors.initials: K
authors.lastname: Saiya-Cork
authors.forename: Roxane
authors.initials: R
authors.lastname: Collins
authors.forename: Brian
authors.initials: B
authors.lastname: Parkin
authors.forename: Peter
authors.initials: P
authors.lastname: Ouillette
authors.forename: Erlene
authors.initials: E
authors.lastname: Kuizon
authors.forename: Lisa
authors.initials: L
authors.lastname: Kujawski
authors.forename: Harry
authors.initials: H
authors.lastname: Erba
authors.forename: Erica
authors.initials: E
authors.lastname: Campagnaro
authors.forename: Kerby
authors.initials: K
authors.lastname: Shedden
authors.forename: Mark
authors.initials: M
authors.lastname: Kaminski
authors.forename: Sami N
authors.initials: SN
authors.lastname: Malek
mesh_terms: D000328:Adult; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D020732:Cytogenetic Analysis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D046228:Microarray Analysis; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054928:Validation Studies as Topic
chemical_list: D011972:Receptor, Insulin