Telomere Length as a Prognostic Parameter in Chronic Lymphocytic Leukemia with Reference to IGV(H) Gene Mutation Status.

Recent studies on the immunoglobulin variable heavy chain (IgV(H)) genes have revealed that B-cell chronic lymphocytic leukemia (B-CLL) consists of at least 2 entities with either somatically mutated or unmutated V(H) genes. Cases with unmutated V(H) genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated V(H) genes, that is, GC experienced or post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Telomerase becomes activated during the GC reaction with an elongation of the GC-B cell telomeres and a strong association exists between V(H) gene mutation status and telomere length in CLL (ie mutated cases have longer telomeres).

These results encouraged us to study telomere length and VH gene mutations in relation to clinical parameters in a large series of B-CLL cases (n=261). Telomere length was assessed by a PCR based method (Cawthon, 2002) showing very good correlation to telomere length data obtained by Southern blotting. Ig gene rearrangements were determined by DNA sequencing. The prognostic information given by the Ig mutation status (mutated vs unmutated) as well as by telomere length ("long" vs "short", cut off at median value) was statistically highly significant (p<0.0001 for both). Interestingly, the prognostic information given by telomere length seemed to be restricted to the Ig mutated CLL cases.

Our data indicate that telomere length must be considered as a relevant prognostic factor of importance for B-CLL. Telomere length determination using the here applied PCR technique is fast and accurate and can easily be established in routine diagnostics.