Telomeres and prognosis in patients with chronic lymphocytic leukaemia

Abstract

In the present study, telomere length, telomerase activity, the mutation load of immunoglobulin variable heavy chain (IGHV) genes, and established prognostic factors were investigated in 78 patients with chronic lymphocytic leukaemia (CLL) to determine the impact of telomere biology on the pathogenesis of CLL. Telomere length was measured by an automated multi-colour flow-FISH, and an age-independent delta telomere length (ΔTL) was calculated. CLL with unmutated IGHV genes was associated with shorter telomeres (p = 0.002). Furthermore, we observed a linear correlation between the frequency of IGHV gene mutations and elongation of telomeres (r = 0.509, p < 0.001). With respect to prognosis, a threshold ΔTL of -4.2 kb was the best predictor for progression-free and overall survival. ΔTL was not significantly altered over time or with therapy. The correlation between the mutational load in IGHV genes and the ΔTL in CLL might reflect the initial telomere length of the putative cell of origin (pre- versus post-germinal center B cells). In conclusion, the ΔTL is a reliable prognostic marker for patients with CLL. Short telomeres and high telomerase activity as occurs in some patients with CLL with a worse prognosis might be an ideal target for treatment with telomerase inhibitors.

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

“…In agreement with the aforementioned study [15], treatment did not seem to have any effect on TL and there was no correlation between TL and need for therapy. Notably, TL in follow-up samples was significantly associated with overall survival (P 5 0.006, not shown in figure) indicating that TL can also be used for prognostication in CLL when analyzed at later time-points during the course of disease.…”

“…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].…”

“…To our knowledge, only two studies have investigated TL in longitudinal samples in a limited number of CLL patients reporting TL shortening [10] or no TL changes [15] over time. Here, we assessed TL in sequential samples in a large subgroup (n 5 119) from our population-based cohort with a long follow-up (median 83 months) to investigate TL stability and its prognostic potential at later time-points.…”

“…Thus, untreated cases with longer telomeres at diagnosis demonstrated the highest attrition rate, whereas cases with short telomeres could show elongated telomeres. Previous studies have reported that CLL cases with short telomeres demonstrate higher telomerase activity levels than cases with long telomeres [8,10,15], indicating a compensatory mechanism to protect the shortest telomeres. It is therefore not surprising that CLL clones with short telomeres demonstrate stabilization and even elongation of telomeres at follow up.…”

Dysregulation of Apoptosis and Proliferation in CLL Cells

“…CLL lymphocytes are characterized by shorter telomeres and higher telomerase activity than normal B lymphocytes, what indicates on a greater number of their divisions in the past (Damle et al, 2004). Additionally, shorter telomeres are associated with genetic aberrations of defavourable prognostic signification, mainly unmutated status of the immunoglobulin heavy chain variable gene (Roos et al, 2008), and correlate with shorter progression-free and overall survival of CLL patients (Sellmann et al, 2011). These observations lead to a possible conclusion, that shorter lymphocyte doubling time -well known marker of the aggressive course of the disease -results from higher proliferation rate of neoplastic cells.…”