IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia.
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 V(H)DJ(H) clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one V(L)J(L) 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).
Bagnara
Davide
D
Department of Experimental Medicine, Human Anatomy Section, University of Genoa, Genoa, Italy.
Callea
Vincenzo
V
Stelitano
Caterina
C
Morabito
Fortunato
F
Fabris
Sonia
S
Neri
Antonino
A
Zanardi
Sabrina
S
Ghiotto
Fabio
F
Ciccone
Ermanno
E
Grossi
Carlo Enrico
CE
Fais
Franco
F
D000368:Aged; D002999:Clone Cells; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019143:Evolution, Molecular; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D014644:Genetic Variation; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008213:Lymphocyte Activation; D008297:Male; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D016415:Sequence Alignment; D027041:Somatic Hypermutation, Immunoglobulin
D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell