Mutation pattern of paired immunoglobulin heavy and light variable domains in CLL B-cells

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BlankMutation pattern of paired immunoglobulin heavy and light variable domains

in chronic lymphocytic leukemia B-cells.

F Ghiotto, P Marcatili, C Tenca, MG Calevo, XJ Yan, E Albesiano, D Bagnara, M

Colombo, G Cutrona, CC Chu, F Morabito, S Bruno, M Ferrarini, A Tramontano, F

Fais, and N Chiorazzi

Mol Med, July 13, 2011;

Department of Experimental Medicine, University of Genoa, Genoa, Italy.

B-cell chronic lymphocytic leukemia (CLL) patients display leukemic clones

bearing either germline or somatically mutated IGHV genes. Most information on

CLL Igs, such as the definition of stereotyped BCRs, was derived from germline

unmutated Igs. In particular, detailed studies on the distribution and nature of

mutations in paired heavy and light chain domains of CLL clones bearing mutated

Igs are lacking. To address the somatic hypermutation dynamics of CLL Igs, we

analyzed the mutation pattern of paired IGHV-D-J and IGK/LV-J rearrangements of

193 leukemic clones that displayed ? 2% mutations in at least one of the two

IGVs (IGHV and/or IGK/LV). The relationship between the mutation frequency in

IGHV and IGK/LV CDRs and FRs was evaluated by correlation analysis. Replacement

® mutation frequency within IGK/LV chain CDRs correlated significantly with

mutation frequency of paired IGHV CDRs in lambda but not kappa isotype CLL

clones. CDRs of IGKV-J rearrangements displayed a lower percentage of R

mutations than IGHVs. The frequency/pattern of mutations in kappa CLL Igs

differed also from that in kappa-expressing normal B cells described in

literature. Instead, the mutation frequency within the FRs of IGHV and either

IGKV or IGLV correlated. Notably, the amount of diversity introduced by replaced

amino acids was comparable between IGHVs and IGKVs. The data indicate a

different mutation pattern between kappa and lambda isotype CLL clones and

suggest an antigenic selection that, in kappa samples, operates against CDR

variation,

PMID: 21785810