title: Variability in the degree of expression of phosphorylated IkappaBalpha in chronic lymphocytic leukemia cases with nodal involvement.
abstract: OBJECTIVE
  Based on previous preliminary observations, we hypothesize that the molecular and clinical variability of chronic lymphocytic leukemia (CLL) reflects differences in the degree of nuclear factor (NF)-kappaB activation, as determined by the expression of phosphorylated IkappaBalpha (p-IkappaBalpha).
  
  
  METHODS
  The expression profile (mRNA and protein expression) was analyzed with the Centro Nacional de Investigaciones Oncologicas Oncochip, a cDNA microarray containing 6386 cancer-related genes, and a tissue microarray (TMA). The results were correlated with the IgV(H) mutational status, ZAP-70 expression, cytogenetic alterations, and clinical outcome.
  
  
  RESULTS
  We found correlations between the presence of p-IkappaBalpha, a surrogate marker of NF-kappaB activation, and changes in the expression profile (mRNA and protein expression) and clinical outcome in a series of CLL cases with lymph node involvement. Activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, was associated with the expression of a set of genes comprising key genes involved in the control of B-cell receptor signaling, signal transduction, and apoptosis, including SYK, LYN, BCL2, CCR7, BTK, PIK3CD, and others. Cases with increased expression of p-IkappaBalpha showed longer overall survival than cases with lower expression. A Cox regression model was derived to estimate some parameters of prognostic interest: IgV(H) mutational status, ZAP-70, and p-IkappaBalpha expression. The multivariate analysis disclosed p-IkappaBalpha and ZAP-70 expression as independent prognostic factors of survival.
  
  
  CONCLUSIONS
  A variable degree of activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, is an identifiable event in CLL, and is correlated with changes in the expression profile and overall survival.
authors.affiliation: Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Rodríguez
authors.forename: Nerea
authors.initials: N
authors.lastname: Martínez
authors.forename: Francisca I
authors.initials: FI
authors.lastname: Camacho
authors.forename: Elena
authors.initials: E
authors.lastname: Ruíz-Ballesteros
authors.forename: Patrocinio
authors.initials: P
authors.lastname: Algara
authors.forename: Juan-Fernando
authors.initials: JF
authors.lastname: García
authors.forename: Javier
authors.initials: J
authors.lastname: Menárguez
authors.forename: Tomás
authors.initials: T
authors.lastname: Alvaro
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Fresno
authors.forename: Fernando
authors.initials: F
authors.lastname: Solano
authors.forename: Manuela
authors.initials: M
authors.lastname: Mollejo
authors.forename: Carmen
authors.initials: C
authors.lastname: Martin
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis* / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis; D016019:Survival Analysis
chemical_list: D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha