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Analysis of DNA methylation profile of Korean chronic lymphocytic leukaemia (CLL) patients with MeDIP-Seq

ABSTRACT: In this study, we performed genome-wide methylation profiling of eight CLL patients and five control subjects, in an Asian cohort. Methyl-CpG-binding domain sequencing (MBD-Seq) was used as the profiling method. Differential methylation analysis identified a number of differentially methylated regions (DMRs) and genes (DMGs). More regions were hypomethylated than were hypermethylated. Promoters contained the highest proportion of DMRs, while distal intergenic and intron regions contained the largest number of DMRs. Gene Ontology, pathway analysis, and network-based prioritization of DMGs were also performed.

ORGANISM(S): Homo sapiens (human)

SUBMITTER: Seungwoo Hwang

PROVIDER: S-BSST661 | biostudies-other |

SECONDARY ACCESSION(S): 31974418

REPOSITORIES: biostudies-other

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Novel genes exhibiting DNA methylation alterations in Korean patients with chronic lymphocytic leukaemia: a methyl-CpG-binding domain sequencing study.

Kim Miyoung M Lee Eunyup E Zang Dae Young DY Kim Hyo Jung HJ Kim Ho Young HY Han Boram B Kim Han-Sung HS Kang Hee Jung HJ Hwang Seungwoo S Lee Young Kyung YK

Scientific reports 20200123 1

Chronic lymphocytic leukaemia (CLL) exhibits differences between Asians and Caucasians in terms of incidence rate, age at onset, immunophenotype, and genetic profile. We performed genome-wide methylation profiling of CLL in an Asian cohort for the first time. Eight Korean patients without somatic immunoglobulin heavy chain gene hypermutations underwent methyl-CpG-binding domain sequencing (MBD-seq), as did five control subjects. Gene Ontology, pathway analysis, and network-based prioritization o ...[more]

PMID: 31974418

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Immunotherapy in Chronic Lymphocytic Leukaemia (CLL).

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DNA methylation profile of Korean CLL patients and normal controls

Project description:We performed genome-wide methylation profiling of CLL in an Asian cohort for the first time. Eight Korean patients without somatic immunoglobulin heavy chain gene hypermutations underwent methyl-CpG binding domain sequencing (MBD-seq), as did five control subjects. Gene Ontology, pathway analysis, and network-based prioritization of differentially methylated genes were also performed. We found more hypomethylated regions (2,062 windows) than hypermethylated regions (777 windows). Promoters contained the highest proportion of differentially methylated regions (DMRs; approximately 0.08%), while distal intergenic and intron regions contained the largest number of DMRs. Protein-coding genes were the most abundant, followed by long noncoding and short noncoding genes. The most significantly dysregulated signaling pathways included immune/cancer-related pathways and B-cell receptor signaling. Among the top 10 hub genes identified via network-based prioritization, four novel candidate genes (UBC, GRB2, CREBBP, and GAB2) had no known relevance to CLL while the other six (STAT3, PTPN6, SYK, STAT5B, XPO1, and ABL1) have previously been linked to CLL in Caucasians. As such, our analysis identified four novel candidate genes of potential significance to Asian patients with CLL.

2020-02-03 | GSE136986 | GEO

Novel genes exhibiting DNA methylation alterations in Korean patients with chronic lymphocytic leukaemia: a methyl-CpG-binding domain sequencing study.

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Adaptive and Innate Cytotoxic Effectors in Chronic Lymphocytic Leukaemia (CLL) Subjects with Stable Disease.

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DNA methylation profile of Korean CLL patients and normal controls

Project description:DNA methylation profile of Korean CLL patients and normal controls

| PRJNA564224 | ENA

Chronic lymphocytic leukaemia.

Project description:Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer.

| S-EPMC5336551 | biostudies-literature

Identification of NOTCH1 bound genes in chronic lymphocytic leukaemia (CLL) cells

Project description:NOTCH1 is mutationally activated in ~15% of cases of chronic lymphocytic leukaemia (CLL), but its role in B-cell development and leukemogenesis is not known. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ~50% of peripheral blood CLL cases lacking gene mutations. We identify a ‘NOTCH1 CLL gene expression signature’ in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival and signal transduction physiology. In particular, we show that MYC is a direct target of NOTCH1 via B-cell specific distal regulatory elements, thus implicating this oncogene in the pathogenesis of the disease.

2017-03-24 | GSE92701 | GEO

Observational evidence from patients diagnosed with chronic lymphocytic leukaemia (CLL) in Finland between 2005-2015 show improved survival over time.

Project description:ObjectivesWe aimed to describe treatment patterns of chronic lymphocytic leukaemia (CLL) patients in routine practice settings, compare overall survival and time-to-next-treatment among patients treated in different time periods (2005-2008, 2009-2013, 2014-2015), and explore associated factors.MethodsThis retrospective cohort study included adult CLL patients from the Finnish Hematology Registry.ResultsIn total, 124 and 64 CLL patients received first- and second-line treatments, respectively. The use of first- and second-line treatments with bendamustine-rituximab (BR) increased, while chlorambucil-based treatments decreased over time. Patients treated in more recent years showed a trend towards longer first- and second-line survival. A trend towards inferior overall survival was detected in first- and second-line treatment with B/BR. First-line time-to-next-treatment was longer for patients treated in the later years towards 2015, while second-line time-to-next-treatment did not improve over time.ConclusionsThis study identified that improved treatment outcomes over time were likely influenced by patient characteristics and treatments, but also through other factors unexplored in this study. Hence, further research on the factors influencing patients' survival over time is needed. In particular, research on using B/BR in clinical practice is warranted.

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Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL).

Project description:B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. Deregulation of the T-cell leukemia/lymphoma 1 oncogene (TCL1) in mouse B cells causes a CD5(+) leukemia similar to aggressive human CLL. To examine the mechanisms by which Tcl1 protein exerts its oncogenic activity in B cells, we performed proteomics experiments to identify its interacting partners. We found that Tcl1 physically interacts with de novo DNA methylthansferases Dnmt3A and Dnmt3B. We further investigated the effects of Tcl1 up-regulation on the enzymatic activity of Dnmt3A and found that Tcl1 overexpression drastically inhibits Dnmt3A function. In addition, B cells from TCL1 transgenic mice showed a significant decrease in DNA methylation compared with WT controls. Similarly, CLL samples with high Tcl1 expression showed a decrease in DNA methylation compared with CLL samples with low Tcl1 expression. Given the previous reports of inactivating mutations of DNMT3A in acute myelogenous leukemia and myelodysplastic syndrome, our results suggest that inhibition of de novo DNA methylation may be a common oncogenic mechanism in leukemogenesis.

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DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy.

Project description:BACKGROUND:In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen. RESULTS:The extent of identified changes in CLL cells versus memory B cells from healthy donors was termed "epigenetic burden" (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed "relapse changes" (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology. CONCLUSIONS:Overall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.

| S-EPMC6889736 | biostudies-literature

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