Short telomeres are associated with inferior outcome, genomic complexity, and clonal evolution in chronic lymphocytic leukemia

Jebaraj, Billy Michael Chelliah; Tausch, Eugen; Landau, Dan A.; Bahlo, Jasmin; Robrecht, Sandra; Taylor-Weiner, Amaro; Bloehdorn, Johannes; Scheffold, Annika; Mertens, Daniel; Böttcher, Sebastian; Kneba, Michael; Jäger, Ulrich; Zenz, Thorsten; Wenger, Michael; Fingerle-Rowson, Guenter; Wendtner, Clemens; Fink, Anna‐Maria; Wu, Catherine J.; Eichhorst, Barbara; Fischer, Kirsten; Hallek, Michael; Döhner, Hartmut; Stilgenbauer, Stephan

doi:10.1038/s41375-019-0446-4

Cited by 20 publications

(36 citation statements)

References 38 publications

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“…Deletion of these genes therefore permits these tumor cell clones to undergo further telomere shortening compared to non-17p-/11q-, without activating cell death pathways. In line with this, short telomere length was found to be associated with the presence of mutations in TP53 ( 37 , 40 , 41 , 43 ) and ATM ( 41 , 43 , 44 ). Cases with 17p- or TP53 mutation but long telomere length were found to have mutated IGHV ( 40 , 43 ).…”

Section: Telomere Length Associations and Prognostic Impact Of Telomesupporting

confidence: 61%

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Jebaraj

Stilgenbauer

2021

Front. Oncol.

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Telomeres are nucleprotein structures that cap the chromosomal ends, conferring genomic stability. Alterations in telomere maintenance and function are associated with tumorigenesis. In chronic lymphocytic leukemia (CLL), telomere length is an independent prognostic factor and short telomeres are associated with adverse outcome. Though telomere length associations have been suggested to be only a passive reflection of the cell’s replication history, here, based on published findings, we suggest a more dynamic role of telomere dysfunction in shaping the disease course. Different members of the shelterin complex, which form the telomere structure have deregulated expression and POT1 is recurrently mutated in about 3.5% of CLL. In addition, cases with short telomeres have higher telomerase (TERT) expression and activity. TERT activation and shelterin deregulation thus may be pivotal in maintaining the minimal telomere length necessary to sustain survival and proliferation of CLL cells. On the other hand, activation of DNA damage response and repair signaling at dysfunctional telomeres coupled with checkpoint deregulation, leads to terminal fusions and genomic complexity. In summary, multiple components of the telomere system are affected and they play an important role in CLL pathogenesis, progression, and clonal evolution. However, processes leading to shelterin deregulation as well as cell intrinsic and microenvironmental factors underlying TERT activation are poorly understood. The present review comprehensively summarizes the complex interplay of telomere dysfunction in CLL and underline the mechanisms that are yet to be deciphered.

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Section: Telomere Length Associations and Prognostic Impact Of Telomesupporting

confidence: 61%

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Jebaraj

Stilgenbauer

2021

Front. Oncol.

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“…However, different telomerase activity between CD49d 2 and CD49d 1 cells can be hypothesized, 46 and that different telomere shortening may occur in follow-up samples cannot be ruled out, as it was reported in CLL cases with clonal evolution. 47 In light of all previous considerations, it was not completely unexpected that bimCD49d CLL patients, even in the presence of a small CD49d 1 subpopulation, followed a clinical outcome similar to that of homCD49d 1 patients in CLL cases treated with conventional chemoimmunotherapy. Of note, both homCD49d 1 and bimCD49d expression retained independent prognostic impact in multivariate models, which included the main clinical and biological prognosticators.…”

Section: Discussionmentioning

confidence: 84%

CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression

Tissino

Pozzo

Benedetti

et al. 2020

Blood

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CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The cutoff value for the extensively validated 30% of positive CLL cells is able to separate CLL patients into 2 subgroups with different prognoses, but it does not consider the pattern of CD49d expression. In the present study, we analyzed a cohort of 1630 CLL samples and identified the presence of ∼20% of CLL cases (n = 313) characterized by a bimodal expression of CD49d, that is, concomitant presence of a CD49d+ subpopulation and a CD49d− subpopulation. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49d+ subpopulation over time after therapy. The CD49d+ subpopulation from CD49d bimodal CLL displayed higher levels of proliferation compared with the CD49d− cells; and was more highly represented in the bone marrow compared with peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49d+ subpopulation exceeded the 30% cutoff or not, experienced clinical behavior similar to CD49d+ CLL, both in chemoimmunotherapy (n = 1522) and in ibrutinib (n = 158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should also be considered to improve the prognostic impact of this biomarker in CLL.

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“…In addition, a recent paper from the German CLL Study Group found an association between short telomere length, TP53 abnormalities, early relapse after chemoimmunotherapy and adverse survival. 33 In particular, cases with 17p-or TP53 mutations had the shortest telomeres length, increase genomic complexity as well as clonal evolution. 33 The challenge of contemporary CLL treatment involves attempts to tailor therapy according to the patients' specific biological risk profile.…”

Section: Discussionmentioning

confidence: 99%

“…33 In particular, cases with 17p-or TP53 mutations had the shortest telomeres length, increase genomic complexity as well as clonal evolution. 33 The challenge of contemporary CLL treatment involves attempts to tailor therapy according to the patients' specific biological risk profile. To responsibly and effectively advance the development of new targeted therapies, novel drugs should be specifically offered to patient subgroups who can gain the greatest benefit compared with established chemoimmunotherapy strategies.…”

Section: Discussionmentioning

confidence: 99%

The combination of complex karyotype subtypes and IGHV mutational status identifies new prognostic and predictive groups in chronic lymphocytic leukaemia

et al. 2019

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BACKGROUND: Complex karyotype (CK) is a heterogeneous category with a negative impact in chronic lymphocytic leukaemia (CLL). Our group has recently reported that CK patients with major structural abnormalities (i.e. CK2) are characterised by a worse prognosis, as compared to other lesions within CK(CK1). METHODS: We performed a multicentre retrospective study to test whether the combination of CK subtypes with IGHV status could be a relevant prognostic and predictive tool. RESULTS: Among 522 patients 13% harboured CK2, 41% CK1 and/or U-IGHV (U-CK1) and 46% M-IGHV without any CK subtypes (M-noCK). After a median follow-up of 5.8 years, CK2 patients had the shortest TTFT (5-year TTFT 31%, 39 and 81%, p < 0.0001) and OS (5-year OS 67%, 85 and 93%, p < 0.0001) as compared to U-CK1 or M-noCK cases, regardless of TP53 abnormalities. CK2 patients also had the worst outcome after chemoimmunotherapy. In fact, the median TTNT after FCR or BR was 1.86 and 4.79 years for CK2 and U-CK1, but not reached for M-noCK patients (p < 0.0005). CONCLUSIONS: We herein suggest that the combined assessment of the IGHV mutational status and CK subtypes refines the prognostication of CLL, allowing to identify M-IGHV patients without any CK subtypes who are characterised by an indolent disease and excellent outcome after chemoimmunotherapy.

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Short telomeres are associated with inferior outcome, genomic complexity, and clonal evolution in chronic lymphocytic leukemia

Cited by 20 publications

References 38 publications

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Telomere Dysfunction in Chronic Lymphocytic Leukemia

CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression

The combination of complex karyotype subtypes and IGHV mutational status identifies new prognostic and predictive groups in chronic lymphocytic leukaemia

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