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POT1 mutations identify inferior outcomes in chronic lymphocytic leukemia and disrupted telomere biology function

ABSTRACT: POT1 mutations identify inferior outcomes in chronic lymphocytic leukemia and disrupted telomere biology function

PROVIDER: PRJNA1087609 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28341530_1.fastq.gz	Fastqsanger.gz
	SRR28341530_2.fastq.gz	Fastqsanger.gz
	SRR28341531_1.fastq.gz	Fastqsanger.gz
	SRR28341531_2.fastq.gz	Fastqsanger.gz
	SRR28341532_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

POT1 mutations identify inferior outcomes in chronic lymphocytic leukemia and disrupted telomere biology function

Project description:Telomere protection 1 (POT1) is an important subunit in the shelterin complex, considered the telomere protector. POT1 dysfunction may lead to telomere length dysregulation and genomic instability. Both germline and somatic POT1 mutations have been identified in CLL patients, suggesting the development of the disease. This study aimedto evaluate the occurrence of POT1 mutations throughout CLL's progression and determine their prognostic significance.

2025-03-14 | GSE261569 | GEO

Somatic Rescue and Cancer Mutations in Telomere Biology Disorders

Project description:Clonal hematopoiesis (CH) in inherited bone marrow failure (BMF) is disease-specific but has been poorly characterized in telomere biology disorders (TBD).We studied the architecture, trajectories, and impact of CH in a cohort of 207 TBD patients and assessed the clinical relevance of molecular signatures linked to telomere dysfunction. Most patients (92%) had known germline mutations in TBD genes. CH was rare in asymptomatic but present in 46% of symptomatic patients, recurrently in PPM1D, POT1, TERT promoter (TERTp), and U2AF1. CH frequency increased with age and was significantly higher than in age- matched controls. CH in PPM1D/TERTp was enriched in TERT patients while CH in POT1 was enriched in TINF2 patients. CH in myelodysplastic syndromes (MDS)-related genes, most commonly splicing factors, was enriched in TERT/TERC patients. CH in TERTp, TP53 ̧ and MDS- related genes associated with poorer survival. Chromosome 1q (Chr1q) gain, and splicing factor gene (dominated by U2AF1S34/Q157R) or TP53 mutations increased the risk of MDS/acute myeloid leukemia (AML) development, regardless of allele burden. Trajectories with successive acquisition of MDS-related CH driven by U2AF1S34/Q157R were maladaptive, while adaptive CH involved branched POT1/PPM1D/TERTp trajectories. U2AF1S34/Q157R compensated aberrant TP53 and interferon-γ pathway activation that contribute to hematopoietic stem cell exhaustion in TBD.

2024-11-21 | GSE249209 | GEO

Human POT1 Prevents Severe Telomere Damage Instability Induced by Homology Directed DNA Repair

Project description:The evolutionarily conserved POT1 protein binds the single stranded G-rich telomeric DNA and has been implicated in telomeric DNA maintenance and the suppression of DNA damage checkpoint signaling. Here, we explore human POT1 function through genetics and proteomics discovering that the complete absence of POT1 leads to severe telomere maintenance defects that had not been anticipated from previous depletion studies. We determine the telomeric proteome upon POT1-loss by implementing an improved telomeric chromatin isolation protocol. Using quantitative proteomics by tandem mass tags (TMT) we identified a large set of proteins involved in nucleic acid metabolism that engage with telomeres upon loss of POT1. Inactivation of the homology directed repair machinery suppresses POT1-loss mediated telomeric DNA defects. Our results unravel as major function of human POT1 the suppression of telomere instability induced by homology directed repair.

2020-10-21 | PXD016826 | Pride

Telomere dysfunction and fusion during the progression of chronic lymphocytic leukaemia: evidence for a telomere crisis

Project description:We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukaemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from individuals with the shortest telomeres revealed limited numbers of repeats at the breakpoint, sub-telomeric deletion and microhomology. Array-CGH analysis of individuals displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. Array CGH was undertaken on six individuals (five CLL stage C and one stage A) that displayed evidence of telomere dysfunction, and four (three CLL stage A and one stage B) that displayed longer and apparently stable telomeres.

2010-05-28 | E-GEOD-22016 | biostudies-arrayexpress

Telomere dysfunction and fusion during the progression of chronic lymphocytic leukaemia: evidence for a telomere crisis

2010-05-28 | GSE22016 | GEO

Genetic dynamics in untreated chronic lymphocytic leukemia patients with either stable or progressive disease: a longitudinal study.

Project description:We investigated at two time points a longitudinal cohort of 27 untreated Chronic Lymphocytic Leukemia (CLL) patients with either stable or progressive disease. The sequenced genes included BCOR, EGR2, HIST1H1E, ITPKB, KRAS, MED12, NRAS, RIPK1, SAMHD1, ATM, BIRC3, BRAF, CHD2, DDX3X, DDX3Y, FBXW7, KIT, KLHL6, MAPK1, MYD88, NOTCH1, PIK3CA, POT1, SF3B1, TP53, XPO1 and ZMYM3, which were previously identified as mutated in CLL studies.

2019-11-05 | E-MTAB-8020 | biostudies-arrayexpress

DNA Methylation Variations and Epigenetic Aging in Telomere Biology Disorders

Project description:DNA methylation profiling of 35 Telomere Biology Disorder (TBD) cases and 20 age-matched controls using the Infinium MethylationEPIC BeadChip arrays (Illumina). The cutoff for methylation differences between the cases and controls was set to |Δβ≥|0.2.

2023-05-10 | GSE224847 | GEO

High-throughput proteomics identifies THEMIS2 as independent biomarker of inferior treatment-free survival in untreated chronic lymphocytic leukemia

Project description:Notwithstanding advances in the prognostication of chronic lymphocytic leukemia (CLL), it remains challenging to distinguish between patients with favorable and unfavorable treatment-free survival (TFS). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we performed large-scale, unbiased characterization of global intracellular protein expression in a cohort of 40 CLL cases (patients with time to first treatment [TTFT] ≤24 months of sampling) and 40 age- and sex-matched CLL controls (patients with TTFT >24 months since sampling). Expression of 3268 proteins was quantified in the cohort. IGHV mutational status and trisomy 12 were most impactful on the CLL proteome. Intriguingly, comparing our results to three recently performed CLL mass-spectrometry screens, we identified four proteins that are strongly and consistently associated with IGHV mutational status: ZAP70, LMNA, FTL and FTH1. Additionally, we found that high intracellular protein levels of THEMIS2, a signaling protein acting downstream of the B-cell receptor, was significantly associated with short TTFT, independently of IGHV and TP53 mutational status (HR 2.47 [95%CI 1.54-3.95], P<0.01). This association was validated on the mRNA and protein level by qPCR and ELISA, respectivelly. Lastly, analysis of an independently generated CLL mass-spectrometry dataset verified the association between THEMIS2 expression and TFS (high THEMIS2, median TFS 4 months, versus low THEMIS2, median TFS not reached, P<0.0001)3. In conclusion, we present a comprehensive characterization of the proteome of untreated CLL. Of note, we identify elevated gene and protein expression of THEMIS2 as putative biomarker of inferior TTFT.

2023-10-24 | PXD036918 | Pride

microbiota of human inferior turbinate

Project description:Analysis of human inferior turbinate microbiota

| PRJEB14731 | ENA

Telomere length effect on genes near the telomere in myoblasts

Project description:We examined differential expression of genes within 10MBs of telomeres in myoblasts with long or short telomeres We offer telomere looping with telomere length as a partial mechanistic explanation for the changes gene expression that is observed. Compare expression of genes within 10MB of the telomere in normal myoblasts with long (15 kb) and short (6 kb) telomeres.

2014-07-17 | E-GEOD-48973 | biostudies-arrayexpress

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