scholarly journals Allele-specific repression of lymphotoxin-α by activated B cell factor-1

2004 ◽  
Vol 36 (4) ◽  
pp. 394-399 ◽  
Author(s):  
Julian C Knight ◽  
Brendan J Keating ◽  
Dominic P Kwiatkowski
Keyword(s):  
B Cell ◽  
Allele Specific ◽  
Lymphotoxin Α

Prevalence and Clinical Significance of the MYD88 (L265P) Somatic Mutation in Patients with Waldenström Macroglobulinemia, IgM-Monoclonal Gammopathy of Undetermined Significance or Other Mature B-Cell Neoplasms.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2667-2667 ◽  
Author(s):  
Marzia Varettoni ◽  
Luca Arcaini ◽  
Silvia Zibellini ◽  
Emanuela Boveri ◽  
Sara Rattotti ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Lymphoproliferative Disorders ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Specific Pcr ◽  
Allele Specific ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p ◽  
Monoclonal Component

Abstract Abstract 2667 Waldenström Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration by lymphoplasmacytic lymphoma associated with a monoclonal component of IgM type in the serum. WM is often preceded by an IgM monoclonal gammopathy of undetermined significance (IgM-MGUS). The cumulative probability of progression of IgM-MGUS to WM or to other lymphoproliferative disorders is approximately 1.5% per year. Other mature B-cell neoplasms such as splenic marginal zone lymphoma (SMZL) and B-cell chronic lymphoproliferative disorders (B-CLPD) can carry an IgM monoclonal component and should therefore be considered in differential diagnosis with WM. In a study based on parallel sequencing of the whole genome of lymphoplasmacytic cells and paired normal tissue from WM patients, Treon et al (Blood. 2011;118:Abstract 300) have identified a highly recurrent somatic mutation with oncogenic activity in the myeloid differentiation primary response (MYD88) gene, leading to a change from leucine to proline at position 265 of the aminoacid sequence [MYD88 (L265P)]. Targeted Sanger resequencing showed MYD88 (L265P) in 90% of WM patients, but only in a minority of patients with IgM-MGUS or other mature B-cell neoplasms such as SMZL. We developed an allele-specific PCR for the MYD88 (L265P) mutation, and studied 58 patients with WM, 77 with IgM-MGUS, 84 with splenic marginal zone lymphoma (SMZL) and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). DNA was obtained from bone marrow cells (n=204) and peripheral blood (n=67). The aims of this study were: i) to assess the prevalence of the mutation in WM, IgM-MGUS, SMZL, and B-CLPD; ii) to analyze the relationship between MYD88 (L265P) mutation and clinical phenotype; iii) to evaluate the impact of the mutation on the risk of progression from IgM-MGUS WM or other lymphoproliferative disorders. The MYD88 (L265P) mutation was detected in 58/58 (100%) patients with WM, either asymptomatic (n=39) or symptomatic (n=18), and in 36/77 (47%) patients with IgM-MGUS. In addition, it was detected in 5/84 (6%) patients with SMZL and in 3/52 (6%) with B-CLPD; of these MYD88 (L265P)-positive subjects, 4 SMZL and 2 B-CLPD patients carried a serum IgM monoclonal component, while the remaining B-CLPD patient carried a double (IgM and IgG) monoclonal component. Compared with IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) had significantly higher levels of IgM (P<.0001), lower levels of IgG (P=.04) and IgA (P=.04), and higher incidence of Bence-Jones proteinuria at diagnosis (P=.002). During the follow-up, 9 patients with IgM-MGUS progressed to WM (7 cases) or to marginal zone lymphoma (2 cases). Using a case-control approach, the risk of evolution of patients with MYD88 (L265P) was significantly higher as compared to that of patients with wild-type MYD88 sequence (OR 4.7, 95% confidence interval 0.8–48.7, P=.047). In conclusion, the findings of this study indicate that: i) the allele-specific PCR we developed is able to detect the MYD88 (L265P) mutation in all patients with WM and in nearly half the patients with IgM-MGUS, and therefore represents a useful diagnostic tool; ii) MYD88 (L265P) is an uncommon molecular lesion in SMZL and in B-CLPD, but is associated with an IgM monoclonal component in the few positive patients, suggesting that some cases of B-CLPD might be included in the spectrum of WM; iii) in IgM-MGUS, the mutation is associated with greater disease burden and higher risk of disease progression, and therefore represents a useful prognostic marker. Disclosures: No relevant conflicts of interest to declare.

Epigenomic Evolution In Diffuse Large B-Cell Lymphomas

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 634-634 ◽  
Author(s):  
Heng Pan ◽  
Yanwen Jiang ◽  
David Redmond ◽  
Kui Nie ◽  
Leandro Cerchietti ◽  
...  
Keyword(s):  
Dna Methylation ◽  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Test ◽  
Normal Tissues ◽  
Epigenetic Diversity ◽  
Allele Specific ◽  
Allele Specific Methylation

Abstract Diffuse Large B-cell Lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. It is a heterogeneous disease in which one third of patients either do not respond to treatment or relapse within five years after chemotherapy. It is unclear whether epigenetic alterations are responsible for B cell lymphomas relapse phenotypes, such as increased aggressiveness and chemoresistance. To investigate how the B cell lymphoma epigenome evolves upon chemotherapy, we used Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) to profile DNA methylation genome-wide in primary matched diagnosis-relapse DLBCL samples. We interrogated 13 pairs of DLBCL diagnosis tumors and their matched relapse samples. In addition, we performed methylation profiling of normal tonsilar B cell subsets (Naïve and germinal center B cells) from two healthy human individuals. ERRBS provided DNA methylation levels at 3-4M CpG sites. When combining methylation levels from all interrogated CpG sites, we observed increased DNA methylation levels at CpG-islands (CGIs; p=3.5e-9, t-test) in DLBCLs compared to normal B cells, and stable or slightly decreasing methylation levels outside of CGIs (>10 kb away from known CGIs; p=0.057, t-test). There was no significant change in average DNA methylation levels from diagnosis to relapse either at CGIs or outside of CGIs. However, when we investigated DNA methylation changes at gene promoters, we identified 107 consistently differentially methylated promoters between diagnosis and relapse (> 10% DNA methylation alteration and p < 0.05, paired t-test). Pathway analysis of the corresponding genes using iPAGE identified several pathways and processes associated with either hyper or hypo-methylated genes in relapse, demonstrating that methylation changes associated with relapse are functionally coherent. For example, several genes with TGF-beta receptor activity displayed lower DNA methylation in relapse. Taking advantage of single CpG resolution and high coverage provided by ERRBS, we then sought to investigate the extent of allele-specific methylation (ASM) levels in normal tissues and DLBCL patients. We found increased ASM levels in DLBCLs compared to normal tissues (p=0.0011, t-test) confirming observations in solid tumors. There was no significant change in ASM levels from diagnosis to relapse (p=0.24, t-test). These results suggest that methylation changes associated with lymphomagenesis might frequently involve one allele only, perhaps due to differential nuclear localization of individual chromosomes. However allele-specific methylation may not play a key role in lymphoma progression. Finally, we investigated whether intra-tumor methylation heterogeneity at diagnosis would predict whether a DLBCL patient would relapse. We quantified intra-tumor methylation heterogeneity using a statistical approach based on the probability that two randomly sampled DNA molecules from the tumor cell populations differ from each other in their methylation pattern. We found decreased intra-sample methylation heterogeneity in DLBCLs compared to normal germinal center B cells (p=1.9e-4, t-test), consistent with the clonal origin of tumors. 12 out of 13 pairs also displayed decreased methylation heterogeneity from diagnosis to relapse, which is also consistent with clonal selection upon chemotherapy treatment. We then performed ERRBS on primary tumors from 8 DLBCL patients who have not relapsed five years after treatment. We found that non-relapse patients displayed significantly lower intra-tumor methylation heterogeneity as compared to that of the relapsed patients (p=0.047, t-test), which suggests that increased epigenetic diversity within a population of tumor cells at diagnosis might fuel the Darwinian evolutionary process underlying relapse. We also looked at genetic clonal heterogeneity based on next-generation sequencing of somatic hypermutation profiles in IGH VDJ sequences, but found no differences between relapsed and not relapsed patients (p=0.22, Wilcoxon test). This suggests that epigenetic heterogeneity plays a more substantial role than clonal heterogeneity in fueling the relapse phenotype. In summary, this study provides the first comprehensive characterization of aberrations in DNA methylation in relapse DLBCLs and identified epigenetic diversity in DLBCLs as a potential predictor of relapse. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical Significance of MYD88 Mutation in Patients with Diffuse Large Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3881-3881 ◽  
Author(s):  
Ritsuko Seki ◽  
Takashi Okamura ◽  
Koteda Satoko ◽  
Kuniki Kawaguchi ◽  
Kei Noumura ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
B Cell ◽  
Clinical Significance ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Wild Type ◽  
Probe System ◽  
Allele Specific ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Mutation of the MYD88 has recently been identified in activated B cell like diffuse large B cell lymphoma (DLBCL) and enhanced cell proliferation systems such as JAK-STAT and NF-kB signaling pathways. However, much remains unclear about its clinical significance. In this study, we developed a highly sensitive and an automatic method utilizing guanine-quenching probes (QP) to detect mutation and investigated the relationship between MYD88 L265P mutation and clinical significance. We amplify a DNA fragment including the mutation to intend for by PCR and associate it with Q-probe with complementary sequence, using the temperature that Q-probe dissociates varying according to a conformity degree of the complementarity sequence. We judge it by detecting the fluorescence to be provided by dissociation. Results were obtained from 1ul of DNA solution(10ng) within 90 min by the method. Detected mutations were identical between QP method and allele-specific PCR (AS-PCR).Eighty-nine patients with a diagnosis of de novo DLBCL made between 1999 and 2014, and treated with CHOP or R-CHOP therapy. We retrospectively analyzed the outcome of 89 patients (age range; 21-88 and 59% were female). The median follow-up time was 4.4 y. Survival analyses were performed using the Kaplan-Meier method. None of the patients had a known history of human immunodeficiency virus infection. MYD88 L265P mutation was both assessed by Q-probe system that can detect low levels of mutant DNA and allele-specific TaqMan polymerase chain reaction assay. We performed the direct sequence method using 3130 Applied Biosystem Genetic Analyzer as antithesis. The cell-of-origin was determined based on immunohistochemical (IHC) stains for CD10, BCL-6 and MUM-1 by Hans' algorithm. MYD88 L265Pmutation was detected in 25.8% (23/89) in various tissues of DLBCL. MYD88 mutations occurred more frequently in males (P<0.05), cases without B symptoms (P<0.05). MYD88 mutation was infrequent in DLBCL arising in lymph nodes (10.6%), but more frequently found in extranodal sites such as testes (83%, 5/6), nasal (75%,9/12), central nervous system (50%,2/4), and leg (100%,1/1). In agreement with recent studies, we found no mutated cases among gastric cases. As somatic mutations in MYD88 was reported to be the most frequent alterations found in non-GCB type, we further analyzed GCB or non-GCB type by IHC. MYD88 mutations were predominantly observed in the non-GCB type (74%, 17/23), compared with 26%, 6/23 in GCB type. Overall survival (OS) for 3 years were 84.2% and 70.2% in patients with wild-type MYD88 and in MYD88 mutation group (P=0.366), respectively. Progression-free survival (PFS) for 3 years, 76.9% and 64.3% in patients with wild type and in mutated group (P=0.156), respectively. However, all four cases with CNS relapse had this mutation, 2 originated from testis, and remained 2 from lymph nodes. Our results confirm the remarkable site-specific occurrence of MYD88 mutation. In addition, Q-probe system for detection of MYD88 mutation was very useful because of its sensitivity and in the case who obtained only a small amount of biopsy specimen. MYD88 L265Ppromotes survival of malignant lymphoid cells through several mechanisms. Further large scale study should be necessary for more understanding of biological and clinical significance of DLBCL patients with MYD88 mutation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Lymphotoxin-α-Deficient Mice Make Delayed, But Effective, T and B Cell Responses to Influenza

2002 ◽  
Vol 169 (9) ◽  
pp. 5236-5243 ◽  
Author(s):  
Frances E. Lund ◽  
Santiago Partida-Sánchez ◽  
Byung O. Lee ◽  
Kimberly L. Kusser ◽  
Louise Hartson ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Responses ◽  
B Cell Responses ◽  
Lymphotoxin Α ◽  
Deficient Mice

scholarly journals Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Marco Cavalli ◽  
Nicholas Baltzer ◽  
Husen M. Umer ◽  
Jan Grau ◽  
Ioana Lemnian ◽  
...  
Keyword(s):  
B Cell ◽  
Allele Specific

Allele-specific expression of the mouse B-cell surface protein CD72 on T cells

1997 ◽  
Vol 45 (3) ◽  
pp. 195-200 ◽  
Author(s):  
William H. Robinson ◽  
Michelle M. Tutt Landolfi ◽  
J. R. Parnes
Keyword(s):  
T Cells ◽  
Cell Surface ◽  
B Cell ◽  
Surface Protein ◽  
Cell Surface Protein ◽  
Specific Expression ◽  
Allele Specific Expression ◽  
Allele Specific

scholarly journals Bone Marrow B Cell Apoptosis During In Vivo Influenza Virus Infection Requires TNF-α and Lymphotoxin-α

2002 ◽  
Vol 169 (11) ◽  
pp. 6193-6201 ◽  
Author(s):  
Lisa M. Sedger ◽  
Sam Hou ◽  
Sarah R. Osvath ◽  
Moira B. Glaccum ◽  
Jacques J. Peschon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Influenza Virus ◽  
Virus Infection ◽  
B Cell ◽  
Cell Apoptosis ◽  
Influenza Virus Infection ◽  
Tnf Α ◽  
Lymphotoxin Α
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