title: A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia.
abstract: BACKGROUND
  MicroRNA expression profiles can be used to distinguish normal B cells from malignant B cells in patients with chronic lymphocytic leukemia (CLL). We investigated whether microRNA profiles are associated with known prognostic factors in CLL.
  
  
  METHODS
  We evaluated the microRNA expression profiles of 94 samples of CLL cells for which the level of expression of 70-kD zeta-associated protein (ZAP-70), the mutational status of the rearranged immunoglobulin heavy-chain variable-region (IgV(H) ) gene, and the time from diagnosis to initial treatment were known. We also investigated the genomic sequence of 42 microRNA genes to identify abnormalities.
  
  
  RESULTS
  A unique microRNA expression signature composed of 13 genes (of 190 analyzed) differentiated cases of CLL with low levels of ZAP-70 expression from those with high levels and cases with unmutated IgV(H) from those with mutated IgV(H) . The same microRNA signature was also associated with the presence or absence of disease progression. We also identified a germ-line mutation in the miR-16-1-miR-15a primary precursor, which caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele. Germ-line or somatic mutations were found in 5 of 42 sequenced microRNAs in 11 of 75 patients with CLL, but no such mutations were found in 160 subjects without cancer (P<0.001).
  
  
  CONCLUSIONS
  A unique microRNA signature is associated with prognostic factors and disease progression in CLL. Mutations in microRNA transcripts are common and may have functional importance.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
authors.forename: George Adrian
authors.initials: GA
authors.lastname: Calin
authors.forename: Manuela
authors.initials: M
authors.lastname: Ferracin
authors.forename: Amelia
authors.initials: A
authors.lastname: Cimmino
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Di Leva
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shimizu
authors.forename: Sylwia E
authors.initials: SE
authors.lastname: Wojcik
authors.forename: Marilena V
authors.initials: MV
authors.lastname: Iorio
authors.forename: Rosa
authors.initials: R
authors.lastname: Visone
authors.forename: Nurettin Ilfer
authors.initials: NI
authors.lastname: Sever
authors.forename: Muller
authors.initials: M
authors.lastname: Fabbri
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Iuliano
authors.forename: Tiziana
authors.initials: T
authors.lastname: Palumbo
authors.forename: Flavia
authors.initials: F
authors.lastname: Pichiorri
authors.forename: Claudia
authors.initials: C
authors.lastname: Roldo
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Cinzia
authors.initials: C
authors.lastname: Sevignani
authors.forename: Laura
authors.initials: L
authors.lastname: Rassenti
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Chang-gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000032:analysis / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D035683:MicroRNAs; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human