IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia

Davide Bagnara, Vincenzo Callea, Caterina Stelitano, Fortunato Morabito, Sonia Fabris, Antonino Neri, Sabrina Zanardi, Fabio Ghiotto, Ermanno Ciccone, Carlo Enrico Grossi, Franco Fais

Research output: Contribution to journalArticlepeer-review

Abstract

Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented VHDJH clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one V LJL rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s).

Original languageEnglish
Pages (from-to)50-58
Number of pages9
JournalBritish Journal of Haematology
Volume133
Issue number1
DOIs
Publication statusPublished - Apr 2006

Keywords

  • Antigen stimulation
  • B-cell chronic lymphocytic leukaemia
  • Clonal evolution
  • Immunoglobulin variable region
  • Somatic hypermutation

ASJC Scopus subject areas

  • Hematology

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