TY - JOUR
T1 - Temporal dynamics of clonal evolution in chronic lymphocytic leukemia with stereotyped IGHV4-34/IGKV2-30 antigen receptors
T2 - longitudinal immunogenetic evidence
AU - Sutton, Lesley-Ann
AU - Kostareli, Efterpi
AU - Stalika, Evangelia
AU - Tsaftaris, Athanasios
AU - Anagnostopoulos, Achilles
AU - Darzentas, Nikos
AU - Rosenquist, Richard
AU - Stamatopoulos, Kostas
PY - 2013/8/28
Y1 - 2013/8/28
N2 - Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset 4 possess distinctive patterns of intraclonal diversification (ID) within their immunoglobulin (IG) genes. Although highly indicative of an ongoing response to antigen(s), the critical question concerning the precise timing of antigen involvement is unresolved. Hence, we conducted a large-scale longitudinal study of eight subset 4 cases totaling 511 and 398 subcloned IG heavy and kappa sequences. Importantly, we could establish a hierarchical pattern of subclonal evolution, thus revealing which somatic hypermutations were negatively or positively selected. In addition, distinct clusters of subcloned sequences with cluster-specific mutational profiles were observed initially; however, at later time points, the minor cluster had often disappeared and hence not been selected. Despite the high intensity of ID, it was remarkable that certain residues remained essentially unaltered. These novel findings strongly support a role for persistent antigen stimulation in the clonal evolution of CLL subset 4.
AB - Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset 4 possess distinctive patterns of intraclonal diversification (ID) within their immunoglobulin (IG) genes. Although highly indicative of an ongoing response to antigen(s), the critical question concerning the precise timing of antigen involvement is unresolved. Hence, we conducted a large-scale longitudinal study of eight subset 4 cases totaling 511 and 398 subcloned IG heavy and kappa sequences. Importantly, we could establish a hierarchical pattern of subclonal evolution, thus revealing which somatic hypermutations were negatively or positively selected. In addition, distinct clusters of subcloned sequences with cluster-specific mutational profiles were observed initially; however, at later time points, the minor cluster had often disappeared and hence not been selected. Despite the high intensity of ID, it was remarkable that certain residues remained essentially unaltered. These novel findings strongly support a role for persistent antigen stimulation in the clonal evolution of CLL subset 4.
KW - Clonal Evolution
KW - Humans
KW - Immunogenetic Phenomena
KW - Immunoglobulin Heavy Chains/genetics
KW - Immunoglobulin kappa-Chains/genetics
KW - Leukemia, Lymphocytic, Chronic, B-Cell/genetics
KW - Receptors, Antigen, B-Cell/genetics
U2 - 10.2119/molmed.2013.00042
DO - 10.2119/molmed.2013.00042
M3 - Article
C2 - 23922244
VL - 19
SP - 230
EP - 236
JO - Molecular medicine
JF - Molecular medicine
SN - 1076-1551
ER -