title: Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features.
abstract: OBJECTIVE
  B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease whose outcome can be foreseen by investigating the mutational status of immunoglobulin heavy chain variable (IGHV) genes. Moreover, a different prognosis was reported for CLL expressing specific IGHV genes in the context or not of stereotyped B-cell receptors. Here we investigated novel associations between usage of specific IGHV genes and clinical features in CLL.
  
  
  METHODS
  Among 1,426 CLL-specific IG-rearrangements, stereotyped B-cell receptor clusters never utilized the IGHV3-23 gene. Given this notion, this study was aimed at characterizing the IGHV3-23 gene in CLL, and identifying the properties of IGHV3-23-expressing CLL.
  
  
  RESULTS
  IGHV3-23 was the second most frequently used (134 of 1,426) and usually mutated (M; 109 of 134) IGHV gene in our CLL series. In the vast majority of M IGHV3-23 sequences, the configuration of the 13 amino acids involved in superantigen recognition was consistent with superantigen binding. Clinically, M IGHV3-23 CLL had shorter time-to-treatment than other M non-IGHV3-23 CLL, and multivariate analyses selected IGHV3-23 gene usage, Rai staging, and chromosomal abnormalities as independent prognosticators for M CLL. Compared with M non-IGHV3-23 CLL, the gene expression profile of M IGHV3-23 CLL was deprived in genes, including the growth/tumor suppressor genes PDCD4, TIA1, and RASSF5, whose downregulation is under control of miR-15a and miR-16-1. Accordingly, relatively higher levels of miR-15a and miR-16-1 were found in M IGHV3-23 compared with M non-IGHV3-23 CLL.
  
  
  CONCLUSIONS
  Altogether, expression of the IGHV3-23 gene characterizes a CLL subset with distinct clinical and biological features.
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bomben
authors.forename: Michele
authors.initials: M
authors.lastname: Dal-Bo
authors.forename: Dania
authors.initials: D
authors.lastname: Benedetti
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Daniela
authors.initials: D
authors.lastname: Marconi
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.forename: Rossana
authors.initials: R
authors.lastname: Maffei
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Maria Ilaria
authors.initials: MI
authors.lastname: Del Principe
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Luciano
authors.forename: Elisa
authors.initials: E
authors.lastname: Sozzi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cattarossi
authors.forename: Antonella
authors.initials: A
authors.lastname: Zucchetto
authors.forename: Francesca Maria
authors.initials: FM
authors.lastname: Rossi
authors.forename: Pietro
authors.initials: P
authors.lastname: Bulian
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.forename: Milena S
authors.initials: MS
authors.lastname: Nicoloso
authors.forename: Massimo
authors.initials: M
authors.lastname: Degan
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
authors.forename: Dimitar G
authors.initials: DG
authors.lastname: Efremov
authors.forename: Giovanni
authors.initials: G
authors.lastname: Del Poeta
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003937:Diagnosis, Differential; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement / Q000502:physiology; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification* / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis
chemical_list: C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D050505:Mutant Proteins