scholarly journals Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking

2020 ◽  
Author(s):  
Aneta Mikulasova ◽  
Marco Trevisan-Herraz ◽  
Kent Fung ◽  
Cody Ashby ◽  
Nefeli Karataraki ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Chromatin Accessibility ◽  
Chromosomal Translocations ◽  
Haematological Malignancies ◽  
B Cell Malignancies ◽  
Super Enhancer ◽  
Breakpoint Detection ◽  
Broad Domain ◽  
T Cell Malignancies

AbstractChromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called super-enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the enhancers of the immunoglobulin heavy chain locus (IGH) and proto-oncogene CCND1 that are common in B-cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B-cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of this locus. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B-cell (MAF, MYC and FGFR3) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs are created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs accompanies the translocation of super-enhancers.

scholarly journals Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers

2021 ◽  
pp. gr.276042.121
Author(s):  
Aneta Mikulasova ◽  
Daniel Kent ◽  
Marco Trevisan-Herraz ◽  
Nefeli Karataraki ◽  
Kent T.M Fung ◽  
...  
Keyword(s):  
B Cell ◽  
Hematological Malignancies ◽  
Chromatin Accessibility ◽  
Chromosomal Translocations ◽  
B Cell Malignancies ◽  
Super Enhancer ◽  
Its Gene ◽  
Breakpoint Detection ◽  
Broad Domain ◽  
T Cell Malignancies

Chromosomal translocations are important drivers of hematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy locus (IGH) and proto-oncogene CCND1 that are common in B cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of its gene body. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B cell (MAF, MYC and FGFR3/NSD2) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.

Immunoglobulin heavy-chain consensus probes for real-time PCR quantification of residual disease in acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2651-2658 ◽  
Author(s):  
John W. Donovan ◽  
Marco Ladetto ◽  
Guangyong Zou ◽  
Donna Neuberg ◽  
Christina Poor ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Cell ◽  
B Cell ◽  
Heavy Chain ◽  
Real Time Pcr ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
B Cell Malignancies ◽  
Normal Cells ◽  
Pcr Method

Tumor-related immunoglobulin heavy-chain (IgH) rearrangements are markers for polymerase chain reaction (PCR) detection of minimal residual disease (MRD) in B-cell malignancies. Nested PCR with patient IgH allele-specific oligonucleotide primers can detect 1 tumor cell in 104 to 106 normal cells. In childhood acute lymphoblastic leukemia (ALL), persistence of PCR-detectable disease is associated with increased risk of relapse. The clinical significance of qualitative PCR data can be limited, however, because patients can harbor detectable MRD for prolonged periods without relapse. Recent studies indicate that a quantitative rise in tumor burden identifies patients who are at high risk for relapse. Therefore, an efficient and reliable PCR method for MRD quantification is needed for ALL patients. We have developed a real-time PCR method to quantify MRD with IgH VH gene family consensus fluorogenically labeled probes. With this method, a small number of probes can be used to quantify MRD in a large number of different patients. The assay was found to be both accurate and reproducible over a wide range and capable of detecting approximately 1 tumor cell in 5 × 104 normal cells. We demonstrate that this methodology can discriminate between patients with persistence of MRD who relapse and those who do not. This technique is generally applicable to B-cell malignancies and is currently being used to quantify MRD in a number of prospective clinical studies at our institution.

t(2; 18) and t(18;22) Variant Chromosomal Translocations in B Cell Malignancies

1992 ◽  
Vol 8 (3) ◽  
pp. 197-200 ◽  
Author(s):  
Marie Francoise Bertheas ◽  
Monique Bachy ◽  
Jean-Pierre Magaud ◽  
Ruth Rimokh ◽  
Christian Vasselon ◽  
...  
Keyword(s):  
B Cell ◽  
Chromosomal Translocations ◽  
B Cell Malignancies

scholarly journals Mechanistic basis for chromosomal translocations at the E2A gene and its broader relevance to human B cell malignancies

Cell Reports ◽  
2021 ◽  
Vol 36 (2) ◽  
pp. 109387
Author(s):  
Di Liu ◽  
Yong-Hwee Eddie Loh ◽  
Chih-Lin Hsieh ◽  
Michael R. Lieber
Keyword(s):  
B Cell ◽  
Chromosomal Translocations ◽  
B Cell Malignancies ◽  
Mechanistic Basis ◽  
Human B Cell

scholarly journals Rearranged Ig Heavy Chain DNA Is Detectable in Cell-Free Blood Samples of Patients With B-Cell Neoplasia

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4953-4960 ◽  
Author(s):  
N. Frickhofen ◽  
E. Müller ◽  
M. Sandherr ◽  
T. Binder ◽  
M. Bangerter ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Lymphoblastic Leukemia ◽  
False Negative ◽  
Immunoglobulin Heavy Chain ◽  
Response To Treatment ◽  
Pcr Analysis ◽  
Plasma Samples ◽  
B Cell Malignancies ◽  
Bulky Disease

Tumor-derived DNA has been shown in various cell-free body fluids. In this study, soluble tumor-derived DNA was analyzed in serum and plasma samples of patients with B-cell malignancies. DNA was extracted from tumor cell specimens as well as serum and plasma samples collected from 110 patients with non-Hodgkin's lymphoma and acute B-precursor lymphoblastic leukemia and was subjected to polymerase chain reaction (PCR) analysis for rearranged immunoglobulin heavy chain DNA. In 54% of serum or plasma samples analyzed at different times before and during treatment, clonal DNA from a rearranged immunoglobulin heavy chain locus was detectable. When examined at diagnosis and before any treatment, clonotypic DNA was found in serum or plasma of 86% of the patients. Serum or plasma from patients with systemic or bulky disease was uniformly PCR positive, whereas clonotypic DNA was also recovered from the serum or plasma from the majority of patients with limited disease stages. Degradation of clonal DNA by nucleases in vitro was shown to be one cause of false-negative PCR results. This technical drawback can be relieved by adding a nuclease inhibitor like EDTA, ie, by using plasma instead of serum for PCR analysis. Treatment of patients with cytotoxic drugs was followed by rapid clearance of DNA from the peripheral blood, suggesting that soluble tumor-derived DNA might be associated with viable and proliferating tumor cells. Follow-up studies showed a close correlation of persisting soluble tumor-derived DNA with resistant disease or early relapse. In summary, these data suggest that tumor-derived DNA can be detected in serum or plasma of the majority of patients with B-cell malignancies and that testing of serum or plasma for tumor-associated DNA may be a novel parameter for monitoring response to treatment.

scholarly journals Rearranged Ig Heavy Chain DNA Is Detectable in Cell-Free Blood Samples of Patients With B-Cell Neoplasia

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4953-4960 ◽  
Author(s):  
N. Frickhofen ◽  
E. Müller ◽  
M. Sandherr ◽  
T. Binder ◽  
M. Bangerter ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Lymphoblastic Leukemia ◽  
False Negative ◽  
Immunoglobulin Heavy Chain ◽  
Response To Treatment ◽  
Pcr Analysis ◽  
Plasma Samples ◽  
B Cell Malignancies ◽  
Bulky Disease

Abstract Tumor-derived DNA has been shown in various cell-free body fluids. In this study, soluble tumor-derived DNA was analyzed in serum and plasma samples of patients with B-cell malignancies. DNA was extracted from tumor cell specimens as well as serum and plasma samples collected from 110 patients with non-Hodgkin's lymphoma and acute B-precursor lymphoblastic leukemia and was subjected to polymerase chain reaction (PCR) analysis for rearranged immunoglobulin heavy chain DNA. In 54% of serum or plasma samples analyzed at different times before and during treatment, clonal DNA from a rearranged immunoglobulin heavy chain locus was detectable. When examined at diagnosis and before any treatment, clonotypic DNA was found in serum or plasma of 86% of the patients. Serum or plasma from patients with systemic or bulky disease was uniformly PCR positive, whereas clonotypic DNA was also recovered from the serum or plasma from the majority of patients with limited disease stages. Degradation of clonal DNA by nucleases in vitro was shown to be one cause of false-negative PCR results. This technical drawback can be relieved by adding a nuclease inhibitor like EDTA, ie, by using plasma instead of serum for PCR analysis. Treatment of patients with cytotoxic drugs was followed by rapid clearance of DNA from the peripheral blood, suggesting that soluble tumor-derived DNA might be associated with viable and proliferating tumor cells. Follow-up studies showed a close correlation of persisting soluble tumor-derived DNA with resistant disease or early relapse. In summary, these data suggest that tumor-derived DNA can be detected in serum or plasma of the majority of patients with B-cell malignancies and that testing of serum or plasma for tumor-associated DNA may be a novel parameter for monitoring response to treatment.

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