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Results for “IGHV”

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6 recordsLinked to original sources
PubMed2025

Methylation-based droplet digital polymerase chain reaction shows high concordance with chronic lymphocytic leukemia IGHV somatic mutation status.

OBJECTIVE: Somatic hypermutation at immunoglobulin heavy chain variable (IGHV) genes, an established prognostic and predictive biomarker for chronic lymphocytic leukemia (CLL), is assessed by gene sequencing. We developed a single methylation-specific droplet digital polymerase chain reaction (methyl-ddPCR) to predict IGHV status in patients with CLL. METHODS: The CLL methylation array and IGHV data from the International Cancer Genome Consortium (ICGC) were used for biomarker discovery. Top-ranked candidate regions were manually screened for PCR primer and probe binding sites. A single methyl-ddPCR was evaluated on an internal cohort of CLLs with mutated (M), unmutated (U), and inconclusive IGHV results originally determined by next-generation sequencing (NGS). RESULTS: Analysis of ICGC data identified array probe cg23844018 as a candidate for the PCR. The corresponding CpG site showed high methylation levels in U-CLL and lower levels in M-CLL. On the internal cohort, a single optimal cutoff correctly classified 104 of 115 U- and M-CLLs (90.4%; area under the curve = 0.96). The PCR data correlated with some prognostic fluorescence in situ hybridization and CLL subset groupings. Limited analysis suggests that the PCR may be able to stratify some patients with CLL who have inconclusive results on IGHV NGS testing. CONCLUSIONS: The methyl-ddPCR showed high concordance with CLL IGHV status in an internal cohort.

Humans↗
PubMed2025

Continuous DNA Methylation Deconvolution-Based Surrogate for B-Cell Differentiation State in CLL.

Chronic Lymphocytic Leukemia (CLL) is clinically divided into IGHV mutated (M-CLL) and IGHV unmutated (U-CLL) subtypes, which are thought to arise from distinct cells of origin along the B-cell differentiation pathway. We measured genome-scale DNA methylation in purified CLL samples ( n = 89) and utilized reference-based cell deconvolution techniques to develop a continuous metric of epigenetic similarity across a B-naive-like to B-memory-like scale (B-Index). B-Index accurately classifies CLL into clinical subtypes (98.8%), has a stronger epigenetic signal than IGHV gene percent identity, and demonstrates additional epigenetic signal within the M-CLL subgroup. We demonstrate that U-CLL is epigenetically more similar to B-memory than B-naive cells and reconcile previous reports of a B-naive-like epigenetic signal. The B-memory-like program of U-CLL is enriched for binding sites of transcription factors related to the germinal center activation pathway. Our findings provide epigenetic evidence for discerning CLL mechanisms of initiation and cell of origin. We also identified an epigenetic signal associated with tumor burden, which may have some relation to viral infections such as Epstein-Barr-Virus. Our cell-type deconvolution-based approach to developing a continuous metric for CLL epigenetic differentiation state can be applied to other tumors with multiple subtypes across differentiation stages.

B-memory-like↗
PubMed1992

Involvement of both HLA and Ig heavy chain haplotypes in human IgA deficiency.

Immunoglobulin-A deficiency (IgA-D) is the most common human Ig class deficiency with an estimated frequency of approximately 1 in 500 in the Swedish population. We investigated the immunoglobulin heavy chain constant region gene segments (IGHC) in 103 individuals with IgA-D and the immunoglobulin heavy chain variable region gene segments (IGHV) in 20 of these, in order to identify a possible molecular basis of the defect. No deletions of IGHV gene segments of the VH2, VH5, and VH6 families or the IGHG genes were observed. In the IGHC, there were, however, differences in the restriction fragment length polymorphism frequencies of IGHG genes where the Bam HI haplotype "H2" [IGHGP, 10 kilobases (kb), IGHG2, 25 kb; and IGHG4, 9.0 kb] was overrepresented. The mean serum levels of IgG4 and IgE were significantly lower in individuals (both IgA-D subjects and healthy controls) homozygous for the H2 haplotype than in individuals homozygous for the H1 haplotype (IGHGP, 8.8 kb, IGHG2, 13.5 kb, and IGHG4, 9.4 kb). IgA-D subjects homozygous for HLA DQB1*0201 (DQw2), a marker that has previously been reported to show a strong association with IgA deficiency, showed a similar reduction of serum levels of IgG4 and IgE as compared with DQB1*0201 negative IgA-D subjects. These findings suggest that the two loci found to be associated with IgA deficiency may act via a common pathway.

Blotting, Southern↗
PubMed2025

Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by highly heterogeneous genomic alterations and altered signaling pathways, with limited studies on its proteome. Our study presents a comprehensive analysis of the proteome and phosphoproteome in B-CLL and CLL-like monoclonal B-cell lymphocytosis (MBL) primary cells. Using high-resolution mass spectrometry, we identified 2970 proteins and 316 phosphoproteins across five tumor samples, including 55 newly identified phosphopeptides (ProteomeXchange-PXD005997). Our multifaceted approach also integrated protein microarrays and western blotting for further data validation in a new patient cohort of 14 patients. Despite sharing 73% of their proteomes, the phosphoproteomes varied significantly among samples, independent of cytogenetic alterations and immunoglobulin heavy variable cluster (IGHV) mutational status. We identified common functional hallmarks in B-CLL and MBL phosphoproteomes, notably tonic signaling (low-level, constitutive signaling) of the B-cell antigen-specific receptor (BCR) and nuclear factor NF-kappa-B (NF-kβ)/signal transducer and activator of transcription 3 (STAT3) pathways. Nine phosphoproteins involved in BCR signaling were further validated, showing a high correlation with early disease stages. Our study advances the field by providing a detailed perspective on the proteome and phosphoproteome of B-CLL cells, revealing signaling pathways crucial for disease development and progression. Integrating diverse proteomics techniques and identifying novel phosphopeptides offers new insights into CLL biology, potentially informing future therapeutic strategies and biomarker development for early diagnosis and personalized treatment.

Humans↗
PubMed1988

Analysis of a T-cell tumor-specific breakpoint cluster at human chromosome 14q32.

Cytogenetic abnormalities involving chromosome 14 band q32 are consistently observed in human T-cell tumors. Patients with ataxia-telangiectasia (AT) are especially prone to development of these tumors, which frequently carry either inversion inv(14)(q11;q32) or translocation t(14;14) (q11;q32) chromosomes. We have previously shown that the cytogenetic breakpoints of one t(14;14)(q11;q32) chromosome and two inv(14)(q11;q32) chromosomes in T-cell tumors from AT and non-AT patients join the T-cell receptor alpha chain locus, at chromosome band 14q11, with a region(s) at 14q32 centromeric of the immunoglobulin heavy chain variable region (VH) gene IGHV. We now show that these two inv(14) breakpoints are linked by 2.1 kb of germ-line 14q32 DNA and that the three breakpoints define, by in situ hybridization analysis, a single locus at chromosome band 14q32.1 located about 15-20 million base pairs on the centromeric side of the IGH locus. Sequence analysis of the 14q32.1 breakpoint regions indicates that abnormal recombination does not universally result from mistaken V-D-J joining (D = diversity region; J = joining region). Therefore, we invoke a tumor selection model to describe the role of the 14q32.1 locus in tumor development.

Base Sequence↗
PubMed2026

To Treat or Not to Treat: Navigating Early-Stage CLL in the Era of Targeted Therapy.

Chronic lymphocytic leukemia (CLL) is most frequently diagnosed at early, asymptomatic stages (Rai 0/Binet A), in which a watch-and-wait strategy remains the standard of care, based on historical trials demonstrating no overall survival benefit from early treatment. Over the past two decades, however, substantial advances in genomic profiling-including immunoglobulin heavy-chain variable region (IGHV) mutational status, TP53 disruption, recurrent gene mutations, and complex karyotype-have uncovered marked biological heterogeneity among early-stage patients and substantially improved prediction of disease progression. In parallel, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax-based combinations have transformed the management of symptomatic CLL, raising renewed interest in whether early intervention might favorably alter the natural history of biologically high-risk disease. In this review, we critically examine the evolution of prognostication in early-stage CLL, integrate contemporary molecular and clinical risk models, and summarize evidence from both historical chemotherapy-era studies and modern early-intervention trials. We discuss key unresolved controversies, including reliance on surrogate endpoints, the risks of overtreatment, and the persistent absence of an overall survival benefit across all early-treatment strategies. Finally, we outline future research priorities, including refined genomic stratification, minimal residual disease-driven (MRD)-driven approaches, and combination targeted therapies currently under investigation. Despite renewed interest in preemptive treatment, available evidence supports continued observation for asymptomatic patients outside clinical trials.

Humans↗