ATM germline variants in a young adult with chronic lymphocytic leukemia: 8 years of genomic evolution
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ABSTRACT:
PROVIDER: EGAS00001006268 | EGA |
REPOSITORIES: EGA
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Project description: Not available
| S-EPMC9174185 | biostudies-literature
Project description:Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals. However, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor immunoglobulin heavy chain (BcR IGH) gene repertoire of 124 CLL patients and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, in 14 CLL patients we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14/16 patients with available samples at diagnosis, the CLL clonotype was already present in the pre-diagnostic samples. Overall, our data indicate that the pre-clinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.
2022-06-01 | GSE178208 | GEO
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
Project description:Genetic and epigenetic changes have provided essential insights into the biology and clinical behavior of chronic lymphocytic leukemia (CLL). Overall, increasing number of chromosomal aberrations are related to disease evolution. Complex karyotype (CK) is defined as presence of at least 3 numerical and/or structural aberrations detected by chromosome banding analysis. CK frequently occur in the context of CLLs with unmutated IGHV (U-CLL) and are associated with mutations in ATM or TP53. In this context, the relationship of karyotype complexity and DNA methylation aberrations in CLL remains largely unexplored. In the present study, we selected a highly curated cohort of 52 U-CLL cases with known karyotypes and ATM and TP53 aberration status. An unsupervised Principal Component Analysis using all the CLL samples showed that there is no specific clustering according to karyotype complexity. Although CK was not a major driver of epigenetic variability, a differential methylation (DM) analysis between CK vs non-CK samples led to a small signature of 59 CpGs, suggesting only a subtle relationship between karyotypic complexity and DNA methylation. We noticed that cases with deletions in ATM and TP53 tend to cluster differently in the first two principal components independently of karyotype complexity. A consensus clustering analysis using the 5,000 most variable CpGs confirmed the two clusters, which were enriched in ATMdel (U-CLL C1, P=0.015) and TP53del/mut (U-CLL C2, P=0.004), respectively. U-CLL C1 was also enriched in ATM mutations (P=0.017) and del(13q) (P=0.007), while U-CLL C2 was also related to trisomy 12 (tri12) (P=0.004). Both clusters showed a similarly unfavorable clinical behavior, both in terms of time to first treatment and overall survival. A DM analysis between them resulted in 4,333 differential CpGs. Surprisingly, despite the fact that all the cases are U-CLLs, and therefore germinal center-inexperienced, 2,150 CpGs were modulated in normal B-cell differentiation. Remarkably, 87% of those CpGs showed that cases in the U-CLL C1 cluster are associated with a DNA methylome of less mature B cells (more similar to NBC) whereas cases in the U-CLL C2 were related to more mature B cells (more similar to MBC). A phylogenetic analysis using previously reported CpGs significant for normal B-cell differentiation confirmed this observation. The remaining DM CpGs between the two clusters were largely related to a de novo DNA hypomethylation signature (n=1,679 CpGs) in the U-CLL C2 cluster. In summary, despite not finding a major relationship between complex karyotype and DNA methylation, we discovered the presence of two epitypes in the U-CLL dataset with distinct genetic profiles and methylation signatures related to different levels of epigenetic imprinting, a finding reinforcing the perception that CLL rises from a continuum of B-cell maturation stages.
2025-08-11 | GSE289415 | GEO
Project description:CLL cells obtained from patients with CLL were treated with MLN4924 to determine whether NFkB transcription targets were affected by the drug.
2013-03-05 | GSE44864 | GEO
Project description:Chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is still incurable despite the development of novel therapeutic strategies. This reflects the incomplete understanding of the pathophysiology of this disease. In order to get more detailed insights into CLL development, we performed a comprehensive proteome analysis of primary human CLL cells and B cells from young and age-matched healthy individuals. For comparison, we also analyzed the chronic B cell leukemia cell line JVM-13 showing rather limited similarity to the primary cells. A principal component analysis comprising 6945 proteins separated these four groups, placing B cells of aged-matched controls between those of young donors and CLL patients. Remarkably, B cells from aged controls displayed significant regulation of proteins related to metabolic processes and stress response in mitochondria such as DLAT, FIS1 and NDUFAB1 as well as DNA repair including RAD9A, MGMT and XPA. Interestingly, these alterations apparently correlating with aging of B cells may also be essential for tumorigenesis and were observed similarly in CLL cells. In CLL cells, in addition, some remarkable unique features like the loss of tumor suppressor molecules PNN and JARID2, and high expression of CCDC88A, PIGR and ID3 otherwise associated with epithelial mesenchymal transition and stemness were determined. Furthermore, while typical hallmarks of cancer such as cell proliferation were hardly apparent for CLL cells, alterations of metabolic enzymes were another outstanding feature in comparison to normal B cells, indicating increased beta-oxidation of fatty acids and increased consumption of glutamine. Targeted metabolomics assays corroborated these results. The present findings identify previously unrecognized features of CLL cells and suggest that aging may be accompanied by proteome alterations functionally relevant for predisposing B cells to transform to CLL cells.
2017-12-05 | PXD006576 | Pride
Project description:Chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is still incurable despite the development of novel therapeutic strategies. This reflects the incomplete understanding of the pathophysiology of this disease. In order to get more detailed insights into CLL development, we performed a comprehensive proteome analysis of primary human CLL cells and B cells from young and age-matched healthy individuals. For comparison, we also analyzed the chronic B cell leukemia cell line JVM-13 showing rather limited similarity to the primary cells. A principal component analysis comprising 6945 proteins separated these four groups, placing B cells of aged-matched controls between those of young donors and CLL patients. Remarkably, B cells from aged controls displayed significant regulation of proteins related to metabolic processes and stress response in mitochondria such as DLAT, FIS1 and NDUFAB1 as well as DNA repair including RAD9A, MGMT and XPA. Interestingly, these alterations apparently correlating with aging of B cells may also be essential for tumorigenesis and were observed similarly in CLL cells. In CLL cells, in addition, some remarkable unique features like the loss of tumor suppressor molecules PNN and JARID2, and high expression of CCDC88A, PIGR and ID3 otherwise associated with epithelial mesenchymal transition and stemness were determined. Furthermore, while typical hallmarks of cancer such as cell proliferation were hardly apparent for CLL cells, alterations of metabolic enzymes were another outstanding feature in comparison to normal B cells, indicating increased beta-oxidation of fatty acids and increased consumption of glutamine. Targeted metabolomics assays corroborated these results. The present findings identify previously unrecognized features of CLL cells and suggest that aging may be accompanied by proteome alterations functionally relevant for predisposing B cells to transform to CLL cells.
2018-01-05 | PXD006572 | Pride
Project description:Acquired resistance of chronic lymphocytic leukemia (CLL) to chemotherapy is an important clinical problem and is often caused by cytogenetic aberrations or gene mutations affecting the ATM-p53 DNA damage response pathway or other pathways. However, there are also a lot of resistant cases without detectable mutations and we decided to check whether there are specific epigenetic changes at the level of DNA methylation that might underlie resistance development in CLL. We used Illumina Infinium HumanMethylation450 BeadChips to obtain DNA methylation profiles of 71 CLL patients with different responses to chemotherapy. Fifty-one patients were subjects of the CLL2O clinical trial and 36 of them were categorized as relapsed/refractory after treatment with fludarabine- or bendamustine-containing regimens, whereas the other 15 patients as well as 20 additional patients not on the trial were untreated at the time of sampling. Although we could not correlate chemoresistance with epigenetic changes, we believe that the dataset is valuable and can be used by researchers to test other hypotheses, especially as the patients are well characterized regarding different prognostic and molecular markers (IGHV mutation status, chromosome aberrations, TP53 mutation status, etc.).
2020-03-13 | GSE136724 | GEO
Project description:MiRNA expression is known to be deregulated in chronic lymphocytic leukemia (CLL). To get insight into miRNA expression pattern in CLL, we compaired miRNA expression profiling of peripheral blood-derived CLL cells and the healthy donor, peripheral blood-derived B-lymphocytes. A set of differentially expressed miRNAs was revealed.
2012-05-02 | GSE31599 | GEO
Project description:Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are only partially known. This is in part due to missing information on the proteome of CLL. We profiled the proteome of 49 diverse CLL samples with data-independent acquisition mass spectrometry (DIA-MS) and related the results to genomic, functional and clinical differences. We found trisomy 12 and IGHV to be major determinants of proteome variation in CLL (1073 and 512 differential proteins). In contrast to reports in other biological systems, the disease driver trisomy 12 was associated with limited protein buffering, a finding that suggests the biological relevance of proteins encoded by chromosome 12 for CLL biology. Protein complex analyses detected functional units involved in BCR/PI3K/AKT signaling in CLL with trisomy 12. We identified the transcription factor complex of STAT1/STAT2 to be up-regulated in IGHV unmutated CLL. We tested the functional relevance of protein expression for associations with response to anticancer drugs, and STAT2 protein expression emerged as a biomarker for the prediction of response to kinase inhibitors including BTK and MEK inhibitors. This study highlights the emerging importance of protein abundance profiling in cancer research and identifies STAT2 protein levels as new key factor in CLL biology.
2021-09-27 | PXD022216 | Pride