title: Mutational status and gene repertoire of IGHV-IGHD-IGHJ rearrangements in Serbian patients with chronic lymphocytic leukemia.
abstract: The mutational status and configuration of immunoglobulin heavy variable (IGHV) gene rearrangements was analyzed in 85 Serbian patients with chronic lymphocytic leukemia (CLL). We found that 55.3% of cases belonged to mutated and 44.7% to unmutated CLL, progressive disease predominating in the unmutated subset. IGHV gene use resembled that obtained for Mediterranean countries, except for underrepresentation of the IGHV4 subgroup in our cohort.
  
  
  BACKGROUND
  Chronic lymphocytic leukemia (CLL) results from the clonal expansion of mature B lymphocytes and is characterized by extreme clinical heterogeneity. One of the most reliable prognostic markers in chronic lymphocytic leukemia (CLL) is the mutational status of immunoglobulin heavy variable (IGHV) genes, which defines 2 subsets, mutated CLL (M-CLL) and unmutated CLL (U-CLL), with different clinical courses. Biased IGHV gene use between M-CLL and U-CLL clones, as well as population differences in the IGHV gene repertoire have been reported.
  
  
  METHODS
  In this study, mutational status and configuration of IGHV-IGHD-IGHJ rearrangements in 85 Serbian patients were analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing methodology.
  
  
  RESULTS
  We found that 55.3% of cases belonged to M-CLL and 44.7% belonged to U-CLL, with progressive disease predominating in the unmutated subset. Most frequently expressed was the IGHV3 subgroup (55.7%), followed by IGHV1 (27.3%), IGHV4 (12.5%), IGHV5 (2.3%), IGHV2 (1.1%), and IGHV6 (1.1%). The distribution of IGHD subgroups was as follows: IGHD3, 39.1%; IGHD2, 21.8%; IGHD6, 12.6%; IGHD1, 10.3%; IGHD4, 8%; IGHD5, 6.9%; and IGHD7, 1.1%. The most frequent IGHJ gene was IGHJ4 (48.9%), followed by IGHJ6 (28.4%), IGHJ3 (11.4%), and IGHJ5 (11.4%). In 15.3% of cases, heavy complementarity-determining region 3 (VH CDR3) amino acid sequences could be assigned to previously defined stereotyped clusters.
  
  
  CONCLUSIONS
  Our study showed a strong correlation between IGHV gene mutational status and clinical course of CLL. IGHV gene use was comparable to that obtained for Mediterranean countries, with the exception of the IGHV4 subgroup, which was underrepresented in our cohort.
authors.affiliation: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
authors.forename: Teodora
authors.initials: T
authors.lastname: Karan-Djurasevic
authors.forename: Vuk
authors.initials: V
authors.lastname: Palibrk
authors.forename: Tatjana
authors.initials: T
authors.lastname: Kostic
authors.forename: Vesna
authors.initials: V
authors.lastname: Spasovski
authors.forename: Gordana
authors.initials: G
authors.lastname: Nikcevic
authors.forename: Sanja
authors.initials: S
authors.lastname: Srzentic
authors.forename: Milica
authors.initials: M
authors.lastname: Colovic
authors.forename: Natasa
authors.initials: N
authors.lastname: Colovic
authors.forename: Ana
authors.initials: A
authors.lastname: Vidovic
authors.forename: Darko
authors.initials: D
authors.lastname: Antic
authors.forename: Biljana
authors.initials: B
authors.lastname: Mihaljevic
authors.forename: Sonja
authors.initials: S
authors.lastname: Pavlovic
authors.forename: Natasa
authors.initials: N
authors.lastname: Tosic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D015321:Gene Rearrangement; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055771:Serbia
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region