Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1-regulated transcription

Edelmann, Jennifer; Holzmann, Karlheinz; Tausch, Eugen; Saunderson, Emily A.; Jebaraj, Billy Michael Chelliah; Steinbrecher, Daniela; Dolnik, Anna; Blätte, Tamara J.; Landau, Dan A.; Saub, Jenny; Estenfelder, Sven; Ibach, Stefan; Cymbalista, Florence; Leblond, Véronique; Delmer, Alain; Bahlo, Jasmin; Robrecht, Sandra; Fischer, Kirsten; Goede, Valentin; Bullinger, Lars; Wu, Catherine J.; Mertens, Daniel; Ficz, Gabriella; Gribben, John G.; Hallek, Michael; Döhner, Hartmut; Stilgenbauer, Stephan

doi:10.3324/haematol.2019.217307

Cited by 34 publications

(39 citation statements)

References 54 publications

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“…Among the recurrently mutated genes in CLL, SF3B1 was found to be associated with short telomere length across different studies ( 37 , 40 , 43 , 45 ). For NOTCH1 mutations, some reports suggested an association ( 37 ) while others found no association ( 40 , 43 ) with telomere length.…”

Section: Telomere Length Associations and Prognostic Impact Of Telomementioning

confidence: 99%

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 Telomementioning

confidence: 99%

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Jebaraj

Stilgenbauer

2021

Front. Oncol.

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“…Previous WGS of relapsed/refractory CLL showed enrichment for TP53, ATM, SF3B1 and NOTCH1 aberrations 76 . Combination of TP53, ATM, CDKN2A/B losses and MYC gains, converging on pathways related to DDR, apoptosis or cell cycle control were identified using SNP arrays in circulating CLL from a multiply relapsed high-risk CLL cohort 74 .…”

Section: Mek and Mapk Pathway Inhibition Remains Unstudied In Rsmentioning

confidence: 99%

“…Mutations in MAPK pathway genes are reported in 8% of CLL, accumulating in poorprognosis cases 31,73 . NOTCH1 signaling, toll-like receptor signaling, and DDR pathway aberrations occur frequently in multiply relapsed and TP53 disrupted CLL 74 . In this study, fifteen patients developed RS during follow-up.…”

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confidence: 99%

Genomic and transcriptomic correlates of Richter transformation in chronic lymphocytic leukemia

Klintman

Appleby

Stamatopoulos

et al. 2021

Blood

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The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter's Syndrome (RS) and it is a rare event with dismal prognosis. In this study, we conducted whole genome sequencing (WGS) of paired circulating CLL (PB-CLL) and RS biopsies (tissue-RS) from 17 clinical trial (CHOP-O) patients. We found that tissue-RS was enriched for mutations in poor-risk CLL drivers and genes in the DNA damage response (DDR) pathway. In addition, we identified genomic aberrations not previously implicated in RS, including the protein tyrosine phosphatase receptor (PTPRD) and tumour necrosis factor receptor associated factor three (TRAF3). In the non-coding genome, we discovered AID-related and unrelated kataegis in tissue-RS affecting regulatory regions of key immune regulatory genes. These include BTG2, CXCR4, NFATC1, PAX5, NOTCH-1, SLC44A5, FCRL3, SELL, TNIP2 andTRIM13. Furthermore, differences between the global mutation signatures of pairs of PB-CLL and tissue-RS samples implicate DDR as the dominant mechanism driving transformation. Pathway-based clonal de-convolution analysis showed that genes in the MAPK and DDR pathways demonstrate high clonal expansion probability. Direct comparison of nodal-CLL and tissue-RS pairs from an independent cohort confirmed differential expression of the same pathways by RNA expression profiling. Our integrated analysis of WGS and RNA expression data significantly extends previous targeted approaches, which were limited by the lack of germline samples, and it facilitates the identification of novel genomic correlates implicated in RS transformation, which could be targeted therapeutically. Our results inform the future selection of investigative agents for a UK clinical platform study (NCT03899337).

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“…Among the known features with clinical relevance in the pathobiology of CLL are the highly genetic mutations acting either independently or in combination with chromosomal rearrangements [ 1 , 5 ]. Driver mutations have been associated with adverse clinical outcomes, and thus serve as biomarkers, indicators of therapeutic options or as potential therapeutic targets ( Table S1 ) [ 2 , 4 , 5 , 6 , 7 , 8 ]. Somatic mutations in immunoglobulin heavy chain variable region gene (IGHV), activating B cell receptor (BCR)-signaling kinases lead to the lower survival and proliferation of CLL cells, providing patients with “mutated” M-CLL, which is a better clinical outcome vs. “unmutated” U-CLL patients [ 2 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite current therapeutic strategies and improvements, there are an increasing number of deaths in accordance with the increasing incidence rates and the second primary malignancies (SPMs) [ 48 , 49 , 50 , 51 , 52 , 53 ]. Unknown genetic risk factors related to specific SMPs in patients, individual complex karyotypes, genetic mutations, altered signaling pathways, individual tumor microenvironments, recurrent expanded or diminished genetic alterations and “ad hoc” therapies, and drugs combinations without restrictive guideline based on characteristic biomarkers, are among some of the reasons [ 3 , 5 , 8 , 36 , 54 ]. The consequences are inadequate drug response, MRD and drug resistance [ 5 , 32 , 36 , 54 ].…”

Section: Introductionmentioning

confidence: 99%

Proteomics and Drug Repurposing in CLL towards Precision Medicine

Mavridou

Psatha

Aivaliotis

2021

Cancers

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CLL is a hematological malignancy considered as the most frequent lymphoproliferative disease in the western world. It is characterized by high molecular heterogeneity and despite the available therapeutic options, there are many patient subgroups showing the insufficient effectiveness of disease treatment. The challenge is to investigate the individual molecular characteristics and heterogeneity of these patients. Proteomics analysis is a powerful approach that monitors the constant state of flux operators of genetic information and can unravel the proteome heterogeneity and rewiring into protein pathways in CLL patients. This review essences all the available proteomics studies in CLL and suggests the way these studies can be exploited to find effective therapeutic options combined with drug repurposing approaches. Drug repurposing utilizes all the existing knowledge of the safety and efficacy of FDA-approved or investigational drugs and anticipates drug alignment to crucial CLL therapeutic targets, leading to a better disease outcome. The drug repurposing studies in CLL are also discussed in this review. The next goal involves the integration of proteomics-based drug repurposing in precision medicine, as well as the application of this procedure into clinical practice to predict the most appropriate drugs combination that could ensure therapy and the long-term survival of each CLL patient.

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Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1-regulated transcription

Cited by 34 publications

References 54 publications

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Genomic and transcriptomic correlates of Richter transformation in chronic lymphocytic leukemia

Proteomics and Drug Repurposing in CLL towards Precision Medicine

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