Association between telomere length and VH gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications

Abstract

The immunoglobulin V H gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL) into two entities with a different clinical course. 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, post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and V H gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between V H gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 6.3 kbp). Shorter telomeres also constituted a subgroup with a worse prognosis than cases with longer telomeres (median survival 59 vs 159 months). Furthermore, the Ig gene sequence data revealed that samples with high mutations frequency (46%) had long telomeres (B8 kbp). Thus, both the telomere and V H gene mutation status in CLL appear linked, which may reflect the proliferative history of the clonal cells with regard to the GC reaction.

Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

“…1 CD38 positivity (P < 0.0001), and 11q/17p deletion (Fig. 1B), as documented earlier by us and others [9][10][11][12][13][14]. For the first time, we observed that mutations in the NOTCH1 and SF3B1 genes were associated with particularly short TL, similar to patients with 11q or 17p deletion (Fig.…”

“…The future status of these biomarkers as a basis for clinical decision makings has not yet been fully defined, although the immunoglobulin heavy chain variable (IGHV) gene mutational status and in particular the presence of certain recurrent genomic aberrations (i.e., 11q2, 112, 13q2, 17p2) are commonly applied biomarkers [5][6][7]. Several studies have lately indicated TL as a potential prognostic marker in CLL, whereby short telomeres may predict poor clinical outcome [8][9][10][11][12][13][14][15]. Furthermore, a strong association has been reported between short TL and IGHV-unmutated CLL [11], and high-risk genomic aberrations such as del(17p) [13].…”

Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia

“…28,29 Previous studies have shown that TL associates with IGHV homology, high-risk cytogenetics and poor TFS. 25,26 Subsequent reports outlined the existence of patients in which discordance exists between TL and IGHV-MS and suggested a superior predictive value of TL. 28,29 Finally, Roos et al 47 were able to link TL with poor cytogenetics in a series of 152 patients, including samples collected both at diagnosis and after treatment.…”

“…A number of reports have shown that short telomeres and expression of h-tert, the catalytic subunit of telomerase, are poor prognostic factors in this neoplasm. [24][25][26][27] Although early studies postulated that telomere length (TL) was mostly acting as a surrogate marker for IGHV-MS, a number of subsequent reports indicated that in discordant cases TL performed better than IGHV-MS, suggesting that TL deserved further consideration as a prognostic biomarker in CLL. 28,29 Despite these encouraging results, additional experience needs to be accumulated on TL as a prognostic marker in CLL.…”

The Immunoglobulin genes and Chronic Lymphocytic Leukemia (CLL)

“…The degree of SHM in the cell may reflect the number of rounds of divisions the cells have undergone in the GC which is supported by a correlation with telomere length and degree of mutations (97). Therefore, it is possible that mutated cells which have divided more frequently during the GC reaction (highly mutated, >5%) may be more anergic/resting post GC when they transform to CLL and therefore represent more benign tumor cells.…”