title: Differential gene expression profile associated to apoptosis induced by dexamethasone in CLL cells according to IGHV/ZAP-70 status.
abstract: OBJECTIVE
  Glucocorticoids are part of the therapeutic armamentarium of chronic lymphocytic leukemia (CLL) where it has been suggested that cells with unmutated IGHV genes exhibit higher sensitivity. The mechanisms by which glucocorticoids are active in CLL are not well elucidated. We aimed to ascertain the activity of dexamethasone in CLL cells according to prognosis and to identify the molecular mechanisms that are influencing the response to this drug.
  
  
  METHODS
  Sensitivity to dexamethasone was analyzed ex vivo in 50 CLL and compared according to IGHV mutational status and/or ZAP-70 expression. The response was further compared by gene expression profiling (GEP) of selected cases. Expression of genes of interest was validated by quantitative reverse transcriptase PCR.
  
  
  RESULTS
  Response to dexamethasone was higher in cases with unmutated IGHV/high ZAP-70 expression, and the levels of induction of the pro-apoptotic Bim protein correlated with the degree of cell death. GEP analysis showed few genes differentially expressed after dexamethasone treatment between mutated and unmutated cases. However, functional annotation analysis showed that unmutated cases had significant enrichment in terms related to apoptosis. Specific analysis of genes of interest conducted in a large series disclosed that in unmutated IGHV cells, FKBP5 expression was higher at baseline and after dexamethasone exposure and that GILZ was more induced by dexamethasone treatment in these cases.
  
  
  CONCLUSIONS
  Unmutated IGHV/high ZAP-70 CLL cells exhibit better response to dexamethasone treatment, which is accompanied by a differential expression of genes involved in the glucocorticoid receptor pathway and by an increased induction of genes related to apoptosis.
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Maria Joao
authors.initials: MJ
authors.lastname: Baptista
authors.forename: Ana
authors.initials: A
authors.lastname: Muntañola
authors.forename: Eva
authors.initials: E
authors.lastname: Calpe
authors.forename: Pau
authors.initials: P
authors.lastname: Abrisqueta
authors.forename: Olga
authors.initials: O
authors.lastname: Salamero
authors.forename: Eva
authors.initials: E
authors.lastname: Fernández
authors.forename: Carles
authors.initials: C
authors.lastname: Codony
authors.forename: Eva
authors.initials: E
authors.lastname: Giné
authors.forename: Susana G
authors.initials: SG
authors.lastname: Kalko
authors.forename: Marta
authors.initials: M
authors.lastname: Crespo
authors.forename: Francesc
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D016000:Cluster Analysis; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D034622:RNA Interference; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D003907:Dexamethasone; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D022021:Tacrolimus Binding Proteins; D014157:Transcription Factors; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099159:Tacrolimus Binding Protein 5; C000606775:BCL2L11 protein, human; C404226:TSC22D3 protein, human