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Blood Cancer Journal Dec 2022A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in... (Review)
Review
A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.
Topics: Humans; Leukemia, Hairy Cell; Neoplasm, Residual; Remission Induction; Genes, Immunoglobulin Heavy Chain; Flow Cytometry
PubMed: 36509740
DOI: 10.1038/s41408-022-00760-z -
Nature Communications Jul 2023Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which...
Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which have not been fully elucidated. Countering models that presume antibodies are generated largely by stochastic processes, we demonstrate that polymorphisms within the immunoglobulin heavy chain locus (IGH) impact the naive and antigen-experienced antibody repertoire, indicating that genetics predisposes individuals to mount qualitatively and quantitatively different antibody responses. We pair recently developed long-read genomic sequencing methods with antibody repertoire profiling to comprehensively resolve IGH genetic variation, including novel structural variants, single nucleotide variants, and genes and alleles. We show that IGH germline variants determine the presence and frequency of antibody genes in the expressed repertoire, including those enriched in functional elements linked to V(D)J recombination, and overlapping disease-associated variants. These results illuminate the power of leveraging IGH genetics to better understand the regulation, function, and dynamics of the antibody response in disease.
Topics: Humans; Genes, Immunoglobulin Heavy Chain; Genes, Immunoglobulin; Alleles; Germ-Line Mutation; Immunoglobulin Heavy Chains
PubMed: 37479682
DOI: 10.1038/s41467-023-40070-x -
A correlation study between IgH gene rearrangement and orbital lymphoma removal operation prognosis.European Review For Medical and... Jun 2017To explore the relationship between IgH gene rearrangement and orbital MALT (mucose-associated lymphoid tissue) lymphoma removal operation prognosis, and to quantify the...
OBJECTIVE
To explore the relationship between IgH gene rearrangement and orbital MALT (mucose-associated lymphoid tissue) lymphoma removal operation prognosis, and to quantify the effect of IgH gene rearrangement on primary orbital MALT lymphoma prognosis.
PATIENTS AND METHODS
Fifty-eight patient cases with primary orbital MALT lymphoma were included in this study. Orbital lymphoma specimens were embedded in paraffin for sectioning. IgH gene rearrangement was detected using PCR. The correlation between IgH gene rearrangement and the patient recurrence and survival rates were determined using statistical analysis. The aforementioned rates were calculated and a survival curve was determined. p-values lower than 0.05 was considered statistically significant.
RESULTS
We found that the 5-year disease-free survival rate was 90.8% in patients with orbital MALT lymphoma (mean value 56.7 months, range 52-60 months). The use of IgH gene rearrangement detection methods found that the non-recurrence rate of primary orbital MALT lymphoma cases was 79.3%. Survival analysis revealed that IgH gene rearrangement was significantly correlated with recurrence of orbital MALT lymphoma (p<0.001).
CONCLUSIONS
IgH gene rearrangement detection can be improved by the combined usage of multiple primer pairs, especially family specific primers. In the future, detection of IgH gene rearrangement may be used as a novel marker to predict the prognosis of patients with primary orbital MALT lymphoma.
Topics: Adolescent; Adult; Aged; Disease-Free Survival; Female; Gene Rearrangement; Genes, Immunoglobulin Heavy Chain; Humans; Lymphoma; Lymphoma, B-Cell, Marginal Zone; Male; Middle Aged; Neoplasm Recurrence, Local; Orbital Neoplasms; Prognosis
PubMed: 28678330
DOI: No ID Found -
Frontiers in Immunology 2018Functional antigen receptor genes are assembled by somatic rearrangements that are largely lymphocyte lineage specific. The immunoglobulin heavy chain () gene locus is...
Functional antigen receptor genes are assembled by somatic rearrangements that are largely lymphocyte lineage specific. The immunoglobulin heavy chain () gene locus is unique amongst the seven antigen receptor loci in undergoing partial gene rearrangements in the wrong lineage. Here we demonstrate that breakdown of lineage-specificity is associated with inappropriate activation of the Eμ enhancer during T cell development by a different constellation of transcription factors than those used in developing B cells. This is reflected in reduced enhancer-induced epigenetic changes, eRNAs, formation of the RAG1/2-rich recombination center, attenuated chromatin looping and markedly different utilization of D gene segments in CD4CD8 (DP) thymocytes. Additionally, CTCF-dependent V locus compaction is disrupted in DP cells despite comparable transcription factor binding in both lineages. These observations identify multiple mechanisms that contribute to lineage-specific antigen receptor gene assembly.
Topics: Animals; B-Lymphocytes; Chromatin; Enhancer Elements, Genetic; Gene Expression Regulation; Genetic Loci; Immunoglobulin Heavy Chains; Introns; Mice; ROC Curve; Thymocytes; V(D)J Recombination
PubMed: 30483245
DOI: 10.3389/fimmu.2018.02426 -
Indian Journal of Hematology & Blood... Mar 2015This study investigates PCR analysis of immunoglobulin heavy chain (IgH) and T cell receptor (TCR) gene rearrangements on paraffin-embedded tissue sections and bone...
This study investigates PCR analysis of immunoglobulin heavy chain (IgH) and T cell receptor (TCR) gene rearrangements on paraffin-embedded tissue sections and bone marrow aspirates of patients suspected to have lymphoproliferative disorders but with inconclusive diagnosis in histopathological examination. 130 samples of patients with inconclusive immunohistochemistry results were evaluated for clonal rearrangement of IgH and TCR genes. Based on histopathology examination, the patients were divided into three groups: the first group without any definite diagnosis of lymphoproliferative disorders (60 cases, 46.2 %), the second group suspected to have a lymphoproliferative disorder but in favor of benign disorders (19 cases, 14.6 %) and the third group suspect to lymphoproliferative disorders but relatively in favor of malignant disorders (51 cases, 39.2 %). After DNA extraction and quality control, semi-nested PCR was performed using consensus primers for amplification of TCR-γ and CDR-3 regions of IgH genes. PCR products were analyzed after heteroduplex analysis using polyacrylamide gel electrophoresis, and were subject to silver staining. Totally, in over half of the cases (55.4 %), a monoclonal pattern was found in IgH or TCR-γ genes rearrangements. Monoclonal IgH gene rearrangement was detected in 48.1 % of patients, whereas monoclonal TCR-γ gene rearrangement was found in 33.6 % of them, which was not statistically significant (P = 0.008). Only in 32 patients (24.6 %) were the results of TCR-γ and IgH gene rearrangements consistent with respect to the presence (2.3 %) or absence (22.3 %) of monoclonality. Finally, PCR analysis of TCR-γ and IgH gene rearrangements led to definite diagnosis in 105 patients (80.8 %), and only 25 cases (19.2 %) remained inconclusive. Our results emphasize the usefulness of gene rearrangement study in cases without a definite diagnosis in immunohistochemistry studies. Multiple PCR analysis results when combined with patient's clinical course and immunohistochemistry can lead to early diagnosis and subsequent therapy.
PubMed: 25548443
DOI: 10.1007/s12288-014-0387-z -
Cancer Control : Journal of the Moffitt... Oct 2015Because chronic lymphocytic leukemia (CLL) typically follows an indolent course, many patients do not need to initiate therapy until they reach a relatively advanced... (Review)
Review
BACKGROUND
Because chronic lymphocytic leukemia (CLL) typically follows an indolent course, many patients do not need to initiate therapy until they reach a relatively advanced age, when frailty and reduced organ function can make some of the standard treatments difficult to tolerate and less effective. However, recent advances in the understanding of CLL biology and the approval of agents in novel treatment classes have offered significant advances in the management of the disease.
METHODS
The author reviewed current treatment goals in CLL management, including issues surrounding complete remission (CR) and minimal residual disease (MRD); the findings of trials of treatments from novel drug classes, primarily kinase inhibitors and monoclonal antibodies; and current strategies for use of standard and novel therapies for treatment of individuals diagnosed with CLL, particularly elderly patients.
RESULTS
Several agents and regimens featuring improved clinical outcomes and tolerability are now available or in advanced development for the management of CLL patients, including the elderly and those with high-risk disease. These include ibrutinib, idelalisib plus rituximab, and obinutuzumab plus chlorambucil.
CONCLUSION
The availability of Bruton's tyrosine kinase inhibitors and phosphatidylinositol 3-kinase inhibitors and other novel therapies will allow elderly CLL patients to receive more efficacious treatment with greater tolerability than available with traditional approaches for management of the disease.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Disease-Free Survival; Frail Elderly; Genes, Immunoglobulin Heavy Chain; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Protein Kinase Inhibitors; Salvage Therapy
PubMed: 26618342
DOI: 10.1177/107327481502204s04 -
Advances in Immunology 2008Immunoglobulin variable region exons are assembled from discontinuous variable (V), diversity (D), and joining (J) segments by the process of V(D)J recombination. V(D)J... (Review)
Review
Immunoglobulin variable region exons are assembled from discontinuous variable (V), diversity (D), and joining (J) segments by the process of V(D)J recombination. V(D)J rearrangements of the immunoglobulin heavy chain (IgH) locus are tightly controlled in a tissue-specific, ordered and allele-specific manner by regulating accessibility of V, D, and J segments to the recombination activating gene proteins which are the specific components of the V(D)J recombinase. In this review we discuss recent advances and established models brought forward to explain the mechanisms underlying accessibility control of V(D)J recombination, including research on germline transcripts, spatial organization, and chromatin modifications of the immunoglobulin heavy chain (IgH) locus. Furthermore, we review the functions of well-described and potential new cis-regulatory elements with regard to processes such as V(D)J recombination, allelic exclusion, and IgH class switch recombination.
Topics: Animals; Chromatin; Epigenesis, Genetic; Exons; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Genes, Immunoglobulin; Humans; Immunoglobulin Class Switching; Recombination, Genetic; Regulatory Sequences, Nucleic Acid; Somatic Hypermutation, Immunoglobulin; VDJ Recombinases
PubMed: 19117530
DOI: 10.1016/S0065-2776(08)00601-9 -
Molecular Immunology Jul 2017Analysis of antibody repertoire development and specific antibody responses important for e.g. autoimmune conditions, allergy, and protection against disease is...
Analysis of antibody repertoire development and specific antibody responses important for e.g. autoimmune conditions, allergy, and protection against disease is supported by high throughput sequencing and associated bioinformatics pipelines that describe the diversity of the encoded antibody variable domains. Proper assignment of sequences to germline genes are important for many such processes, for instance in the analysis of somatic hypermutation. Germline gene inference from antibody-encoding transcriptomes, by using tools such as TIgGER or IgDiscover, has a potential to enhance the quality of such analyses. These tools may also be used to identify germline genes not previously known. In this study, we exploited such software for germline gene inference and define aspects of analysis settings and pre-existing knowledge of germline genes that affect the outcome of gene inference. Furthermore, we demonstrate the capacity of IGHJ and IGHD haplotype inference, whenever subjects are heterozygous with respect to such genes, to lend support to IGHV gene inference in general, and to the identification of novel alleles presently not recognized by germline gene reference directories. We propose that such haplotype analysis shall, whenever possible, be used in future best practice to support the outcome of germline gene inference. IGHJ-directed haplotype inference was also used to identify haplotypes not expressing some IGHV germline genes. In particular, we identified a haplotype that did not express several major germline genes such as IGHV1-8, IGHV3-9, IGHV3-15, IGHV1-18, IGHV3-21, and IGHV3-23. We envisage that haplotype analysis will provide an efficient approach to identify subjects for further studies of the link between the available immunoglobulin repertoire and outcomes of immune responses.
Topics: Alleles; Antibodies; Genes, Immunoglobulin; Genes, Immunoglobulin Heavy Chain; Haplotypes; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Multigene Family; Mutation; Transcriptome
PubMed: 28388445
DOI: 10.1016/j.molimm.2017.03.012 -
Cell Reports Sep 2023To produce a diverse antibody repertoire, immunoglobulin heavy-chain (Igh) loci undergo large-scale alterations in structure to facilitate juxtaposition and...
To produce a diverse antibody repertoire, immunoglobulin heavy-chain (Igh) loci undergo large-scale alterations in structure to facilitate juxtaposition and recombination of spatially separated variable (V), diversity (D), and joining (J) genes. These chromosomal alterations are poorly understood. Uncovering their patterns shows how chromosome dynamics underpins antibody diversity. Using tiled Capture Hi-C, we produce a comprehensive map of chromatin interactions throughout the 2.8-Mb Igh locus in progenitor B cells. We find that the Igh locus folds into semi-rigid subdomains and undergoes flexible looping of the V genes to its 3' end, reconciling two views of locus organization. Deconvolution of single Igh locus conformations using polymer simulations identifies thousands of different structures. This heterogeneity may underpin the diversity of V(D)J recombination events. All three immunoglobulin loci also participate in a highly specific, developmentally regulated network of interchromosomal interactions with genes encoding B cell-lineage factors. This suggests a model of interchromosomal coordination of B cell development.
Topics: B-Lymphocytes; Immunoglobulins; V(D)J Recombination; Genes, Immunoglobulin Heavy Chain; Precursor Cells, B-Lymphoid
PubMed: 37676766
DOI: 10.1016/j.celrep.2023.113074 -
Blood Advances Jul 2022Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is a heterogeneous disease in which the role of immunoglobulin heavy-chain genes (IGHs) remains...
Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is a heterogeneous disease in which the role of immunoglobulin heavy-chain genes (IGHs) remains unknown. To determine the clinical relevance of the IGH repertoire in patients with LPL/WM, we performed immunoglobulin gene rearrangement and complementarity determining region 3 (CDR3) analysis. The IGH variable gene (IGHV) repertoire was remarkably biased in LPL/WM. IGHV3-23, IGHV4-34, IGHV3-30, IGHV3-7, and IGHV3-74 accounted for one-half of the cohort's repertoire. Most cases (97.1%) were found to carry mutated IGHV genes, based on a 98% IGHV germline homology cutoff. IGHV3-30 was associated with long heavy chain CDR3, indicating there was specific antigen selection in LPL/WM. Patients with IGHV3-7 were significantly more likely to harbor the 6q deletion (P < .001) and an abnormal karyotype (P = .004). The IGHV hypermutation rate in patients with the MYD88 L265P mutation was significantly higher than that of wild-type patients (P = .050). IGHV3-23 and IGHV3-74 segments were more frequently detected in patients with MYD88-mutated LPL/WM (P = .050), whereas IGHV3-7 presented more frequently in MYD88 wild-type patients (P = .042). Patients with IGHV4, especially IGHV4-34, had higher levels of lactate dehydrogenase, and IGHV4 was a predictive marker of shorter progression-free survival. These results showed for the first time that the IGHV repertoire has clinical relevance in LPL/WM.
Topics: Complementarity Determining Regions; Genes, Immunoglobulin Heavy Chain; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Myeloid Differentiation Factor 88; Waldenstrom Macroglobulinemia
PubMed: 35537114
DOI: 10.1182/bloodadvances.2022007279