scholarly journals CRIS: Complete Reconstruction of Immunoglobulin V-D-J Sequences from RNA-seq data

2021 ◽  
Author(s):  
Rashedul Islam ◽  
Misha Bilenky ◽  
Andrew P Weng ◽  
Joseph M Connors ◽  
Martin Hirst
Keyword(s):  
B Cell ◽  
De Novo ◽  
Somatic Hypermutation ◽  
Gene Segment ◽  
Chronic Lymphocytic Leukemia Patient ◽  
Lymphocytic Leukemia ◽  
Supplementary Information ◽  
Immunoglobulin Gene ◽  
Rna Seq ◽  
Ighv Gene

Abstract Motivation B-cells display remarkable diversity in producing B-cell receptors through recombination of immunoglobulin V-D-J genes. Somatic hypermutation of immunoglobulin heavy chain variable (IGHV) genes are used as a prognostic marker in B-cell malignancies. Clinically, IGHV mutation status is determined by targeted Sanger sequencing which is a resource intensive and low-throughput procedure. Here we describe a bioinformatic pipeline, CRIS (Complete Reconstruction of Immunoglobulin IGHV-D-J Sequences) that uses RNA sequencing (RNA-seq) datasets to reconstruct IGHV-D-J sequences and determine IGHV somatic hypermutation status. Results CRIS extracts RNA-seq reads aligned to immunoglobulin gene (Ig) loci, performs assembly of Ig-transcripts and aligns the resulting contigs to reference Ig sequences to enumerate and classify somatic hypermutations in the IGHV gene sequence. CRIS improves on existing tools that infer the B-cell receptor (BCR) repertoire from RNA-seq data using a portion IGHV gene segment by de novo assembly. We show that the somatic hypermutation status identified by CRIS using the entire IGHV gene segment is highly concordant with clinical classification in three independent chronic lymphocytic leukemia patient cohorts. Availability The CRIS pipeline is available under the MIT License from https://github.com/Rashedul/CRIS. Supplementary information Supplementary data are available at Bioinformatics Advances online.

scholarly journals Immunoglobulin gene analysis in chronic lymphocytic leukemia in the era of next generation sequencing

Leukemia ◽  
2020 ◽  
Vol 34 (10) ◽  
pp. 2545-2551 ◽  
Author(s):  
Frédéric Davi ◽  
◽  
Anton W. Langerak ◽  
Anne Langlois de Septenville ◽  
P. Martijn Kolijn ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Hypermutation ◽  
Technological Development ◽  
Data Interpretation ◽  
Medical Diagnostics ◽  
Lymphocytic Leukemia ◽  
Immunoglobulin Gene ◽  
New Era ◽  
Ighv Gene ◽  
Therapeutic Decision Making

Abstract Twenty years after landmark publications, there is a consensus that the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is an important cornerstone for accurate risk stratification and therapeutic decision-making in patients with chronic lymphocytic leukemia (CLL). The IGHV SHM status has traditionally been determined by conventional Sanger sequencing. However, NGS has heralded a new era in medical diagnostics and immunogenetic analysis is following this trend. There is indeed a growing demand for shifting practice and using NGS for IGHV gene SHM assessment, although it is debatable whether it is always justifiable, at least taking into account financial considerations for laboratories with limited resources. Nevertheless, as this analysis impacts on treatment decisions, standardization of both technical aspects, and data interpretation becomes essential. Also, the need for establishing new recommendations and providing dedicated education and training on NGS-based immunogenetics is greater than ever before. Here we address potential and challenges of NGS-based immunogenetics in CLL. We are convinced that this perspective helps the hematological community to better understand the pros and cons of this new technological development for CLL patient management.

scholarly journals Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia

2015 ◽  
Vol 112 (14) ◽  
pp. 4322-4327 ◽  
Author(s):  
James S. Blachly ◽  
Amy S. Ruppert ◽  
Weiqiang Zhao ◽  
Susan Long ◽  
Joseph Flynn ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Maturation Stage ◽  
Rna Seq ◽  
Mutation Status ◽  
General Test

Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 1012) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL.

scholarly journals Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3088-3095 ◽  
Author(s):  
Anastasia Hadzidimitriou ◽  
Andreas Agathangelidis ◽  
Nikos Darzentas ◽  
Fiona Murray ◽  
Marie-Helene Delfau-Larue ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Germ Line ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Gene Repertoire ◽  
Immunoglobulin Gene ◽  
Ighv Gene ◽  
Mantle Cell ◽  
Selection Of

Abstract We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were “MCL-biased.” In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases.

Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1524-1533 ◽  
Author(s):  
Fiona Murray ◽  
Nikos Darzentas ◽  
Anastasia Hadzidimitriou ◽  
Gerard Tobin ◽  
Myriam Boudjogra ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Distinctive Features ◽  
Ighv Gene ◽  
Gene Usage

Abstract Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, “stereotyped” amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).

scholarly journals Regulation and a possible stage-specific function of Oct-2 during pre-B-cell differentiation.

1991 ◽  
Vol 11 (10) ◽  
pp. 4885-4894 ◽  
Author(s):  
C L Miller ◽  
A L Feldhaus ◽  
J W Rooney ◽  
L D Rhodes ◽  
C H Sibley ◽  
...  
Keyword(s):  
B Cell ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
De Novo ◽  
Interleukin 1 ◽  
Transcriptional Level ◽  
Immunoglobulin Gene ◽  
B Cell Differentiation ◽  
Nf Kappa B ◽  
Specific Expression

The Oct-2 gene appears to encode a developmental regulator of immunoglobulin gene transcription. We demonstrate that the Oct-2 gene is expressed at low levels in a variety of transformed pre-B-cell lines and is induced specifically in these cells by lipopolysaccharide signalling. This work extends an earlier observation in the pre-B-cell line 70Z/3 and therefore suggests that the inducible expression of the Oct-2 gene, like that of the kappa gene, is a characteristic feature of the pre-B stage of B-cell development. In 70Z/3 cells, the lymphokine interleukin-1 also induces the expression of the Oct-2 and kappa loci. Interestingly, expression of the Oct-2 gene is rapidly induced at the transcriptional level and may not require de novo protein synthesis. Since the changes in the activity of the Oct-2 locus completely correlate with the changes of the activity of the kappa locus, the two genes may be transcriptionally regulated by a common trans-acting factor. In 70Z/3 cells, transforming growth factor beta, an inhibitor of kappa-gene induction, blocks the upregulation of Oct-2 but not the activation of NF-kappa B. These results suggest that the combinatorial action of increased levels of Oct-2 and activated NF-kappa B may be necessary for the proper stage-specific expression of the kappa locus.

Chronic Lymphocytic Leukemia Patient Clustering Based on Somatic Hypermutation (SHM) Analysis

2017 ◽  
pp. 127-138 ◽  
Author(s):  
Eleftheria Polychronidou ◽  
Aliki Xochelli ◽  
Panagiotis Moschonas ◽  
Stavros Papadopoulos ◽  
Anastasia Hatzidimitriou ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Hypermutation ◽  
Chronic Lymphocytic Leukemia Patient ◽  
Lymphocytic Leukemia ◽  
Leukemia Patient

scholarly journals A single pre-B cell can give rise to antigen-specific B cells that utilize distinct immunoglobulin gene rearrangements.

1990 ◽  
Vol 172 (3) ◽  
pp. 815-825 ◽  
Author(s):  
A J Caton
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Clone ◽  
Gene Segment ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Immune Repertoire ◽  
Influenza Virus Hemagglutinin ◽  
Immunoglobulin Gene Rearrangements

A group of hybridomas that express antibodies with related specificities for the influenza virus hemagglutinin (HA), that represent B cells that were the clonal progeny of a single pre-B cell, and that utilized distinct L chain gene rearrangements have been characterized. The clonal relationship was established by the sharing of H chain gene rearrangements at both the productive and the nonproductive alleles. Among these hybridomas, one group had rearranged only one of its kappa alleles, having joined a V kappa 24 gene to the J kappa 2 gene segment. The other group utilized the same V kappa 24 gene segment in productive rearrangement to the J kappa 5 gene segment, and shared an aberrant rearrangements among members of the same B cell clone can normally occur, and can contribute to the generation and diversification of the immune repertoire that is available for the recognition of foreign antigens. Mechanisms by which the distinct rearrangements expressed by the hybridomas might have been generated are discussed.

scholarly journals De Novo CD5+ Diffuse Large B-Cell Lymphomas Express VH Genes With Somatic Mutation

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1145-1151 ◽  
Author(s):  
Masanori Taniguchi ◽  
Kouji Oka ◽  
Atsunori Hiasa ◽  
Motoko Yamaguchi ◽  
Toshiyuki Ohno ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Cellular Origin ◽  
Vh Gene ◽  
Vh Genes ◽  
Large B Cell

Abstract To clarify the cellular origin of de novo CD5+ diffuse large B-cell lymphoma (CD5+ DLBL), particularly in comparison with other CD5+ B-cell neoplasms such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), we analyzed the nucleotide sequence of the Ig heavy chain variable region (IgVH) genes of de novo CD5+ DLBL cases. All 4 cases examined had extensive somatic mutations in contrast with CLL or MCL. The VH gene sequences of de novo CD5+ DLBL displayed 86.9% to 95.2% homology with the corresponding germlines, whereas those of simultaneously analyzed CLL and MCL displayed 97.6% to 100% homology. The VH family used was VH3 in 1 case, VH4 in 2 cases, and VH5 in 1 case. In 2 of 4 examined cases, the distribution of replacement and silent mutations over the complementarity determining region and framework region in the VH genes was compatible with the pattern resulting from the antigen selection. Clinically, CD5+DLBL frequently involved a variety of extranodal sites (12/13) and lymph node (11/13). Immunophenotypically, CD5+ DLBL scarcely expressed CD21 and CD23 (3/13 and 2/13, respectively). These findings indicate that de novo CD5+ DLBL cells are derived from a B-1 subset distinct from those of CLL or MCL.

Aberrant Somatic Hypermutation in Extranodal Marginal Zone B-Cell Lymphoma of MALT Type.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 417-417 ◽  
Author(s):  
Alexander Deutsch ◽  
Ariane Aigelsreiter ◽  
Christine Beham-Schmid ◽  
Alfred Beham ◽  
Werner Linkesch ◽  
...  
Keyword(s):  
B Cell ◽  
Malt Lymphoma ◽  
Marginal Zone ◽  
De Novo ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Chromosomal Translocations ◽  
Genome Wide ◽  
Balanced Translocations

Abstract Extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) accounts for approximately 7% to 8% of all non-Hodgkin lymphomas (NHLs) being the third most frequent histological subtype. The gastrointestinal tract - particularly the stomach - is the most common site of MALT lymphoma comprising 50% of all cases, but virtually every organ may be affected by this type of lymphoma. Transformation (or de novo emergence at extranodal sites) in diffuse large B-cell lymphoma (DLBCL) occurs but - according to the WHO criteria - is considered as separate entity. The understanding of the molecular biology of MALT lymphoma has significantly improved following the recent cloning of recurrent balanced translocations such as t(11;18) or t(14;18), but a mechanism for genome-wide instability during MALT lymphomagenesis has not been described. We have reported that the somatic hypermutation process (SHM) physiologically aimed at mutating the immunoglobulin variable gene (IgV) aberrantly targets multiple proto-oncogenes in >50% of DLCBL (Pasqualucci et al., Nature412:341, 2001). Consequently, multiple mutations are introduced in the 5′ region of genes including known proto-oncogenes such as PIM-1, PAX-5, Rho/TTF and c-MYC. To further investigate whether aberrant somatic hypermutation (ASHM) also occurs in MALT lymphoma, we studied the mutation profile of these genes in 17 MALT lymphomas (6 of gastric- and 11 of nongastric origin) and 18 extranodal DLBCL (10 gastric, 8 nongastric). Mutations in one or more genes were detected in 15 of 17 (88.2%) cases of MALT lymphoma and in all of 18 (100%) cases of extranodal DLBCL. 7 of 17 (41.2%) and 15 of 18 (83.3%) carried mutations in two or more genes in the MALT- and DLBC-lymphoma group, respectively. Overall, mutations in PIM-1 occurred in 5 of 17 (29.4%) cases with MALT lymphoma and in 10 of 18 (55.5%) in extranodal DLBCL cases. For PAX-5, the distribution of mutated cases between MALT- and DLBC-lymphoma was 6 of 17 (35.3%) and 10 of 18 (55.5%), for Rho/TTF 3 of 17 (17.6%) and 8 of 18 (44.4%) and for c-MYC 9 of 17 (52.9%) and 12 of 18 (66.6%), respectively. A total of 99 sequence variants were found in 35 cases, 29 in the MALT lymphomas and 70 in extranodal DLBCL. Although the mutations were almost exclusively single base pair substitutions (n=98 ), an insertion was also present (n=1). Mutations were of somatic origins, occur independent of chromosomal translocations to the Ig loci and share features of the IgV SHM process including bias for transition over transversion, preferential hotspot (RGYW/WRCY) targeting and restriction to the first 1–2Kb from the promoter. The mean mutation frequency in mutated MALT lymphomas was with 0.045 x10−2/bp 1.7 fold lower compared to 0.08 x10−2/bp in mutated extranodal DLBCL. Further in PIM-1, PAX-5 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. These data indicate that aberrant SHM is associated with extranodal DLBCL and MALT lymphoma, likewise. By mutating regulatory and coding sequences of the targeted genes and by possibly favouring chromosomal translocations ASHM may represent a major contributor to their pathogenesis. ASHM may further support a model of MALT lymphomagenesis leading from an antigen driven lesion to transformed MALT lymphoma finally evolving to overt DLBCL.

Usage of IGHV4-39 with Stereotypic B Cell Receptor Is An Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 778-778
Author(s):  
Davide Rossi ◽  
Valeria Spina ◽  
Michaela Cerri ◽  
Clara Deambrogi ◽  
Lorenzo De Paoli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Control Analysis ◽  
Ighv Gene ◽  
Gene Usage

Abstract Richter’s syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma, mainly occurring as diffuse large B-cell lymphoma (DLBCL). The biology of CLL transformation to RS is poorly understood and knowledge on risk factors of RS development is scant. We tested whether IGHV gene usage and stereotypic B cell receptor (BCR) at CLL diagnosis have an impact on RS transformation. The first step of the study consisted of a case-control analysis comparing IGHV gene usage and prevalence of stereotypic HCDR3 in RS (n=69; all DLBCL) versus a control group (n=715) of CLL that had not transformed to RS. The second step consisted of an actuarial assessment of the impact of IGHV gene usage and stereotypic HCDR3 at CLL diagnosis, on the risk of subsequent transformation to RS in a cohort of 754 CLL, of which 39 had transformed to RS. Comparison of IGHV usage in unmutated RS versus unmutated control CLL documented that IGHV4-39 was the sole gene preferentially utilized (6/48, 12.5% vs 5/277, 1.8%, respectively, p=.002) by RS. Prevalence of stereotypic HCDR3 was significantly higher in RS compared to non-transformed CLL when considering all cases (RS: 50.7% vs non-transformed CLL: 22.2%; p<.000001), unmutated cases only (RS: 58.3% vs non-transformed CLL: 35.7%; p=.003), and mutated cases only (RS: 33.3% vs non-transformed CLL: 13.7%; p=.022). Compared to non-transformed CLL, RS preferentially utilized BCR belonging to a subset characterized by rearrangement of unmutated IGHV4-39/IGHD6-13/IGHJ5 genes (2/159, 1.2% vs 5/35, 14.3%, respectively; p=.002). All cases with stereotypic IGHV4-39 carried +12 as the sole FISH abnormality. After a median follow-up of 41.1 months, 39/754 CLL had transformed to RS. Univariate analysis documented: shorter time to transformation in CLL utilizing IGHV4-39 (5-year risk: 35.4%) compared to CLL utilizing other IGHV genes (5-year risk: 5.6%) (p<.000001); higher risk of RS in CLL utilizing stereotypic HCDR3 (5-year risk: 14.2%) compared to CLL without stereotypic HCDR3 (5-year risk: 3.9%) (p<.00001). CLL with stereotypic HCDR3 and IGHV homology 98% showed a significantly higher risk of transformation (5-year risk: 18.4%) compared to CLL with IGHV homology 98% but without stereotypic HCDR3 (5-year risk: 6.8%) (p=.006). Also, stereotypic HCDR3 identified a CLL subgroup that, despite presenting with IGHV homology <98%, showed an increased risk of RS (p=.040). This observation indicates that stereotypic HCDR3 is not a surrogate of IGHV homology for RS prediction. We then tested the independent predictive value for RS transformation of IGHV4-39 usage and of stereotypic HCDR3. Multivariate analysis selected IGHV4-39 usage (HR: 4.25; p=.002) and stereotypic HCDR3 at CLL diagnosis (HR: 3.08; p=.002) as independent predictors of RS transformation. The observation that all RS utilizing IGHV4-39 carried stereotypic HCDR3 prompted investigation of the interaction between IGHV4-39 usage and stereotypic HCDR3 in the model. Multivariate analysis selected the interaction between IGHV4-39 usage and stereotypic HCDR3 at CLL diagnosis as the strongest independent predictor of RS transformation (HR: 5.13; p=.001). The relevance of the interaction between IGHV4-39 and stereotypic HCDR3 was confirmed by bivariate log rank analysis. Accordingly, CLL utilizing both IGHV4-39 and stereotypic HCDR3 were identified as the disease category with highest risk of transformation (5-year risk: 68.7%). Transformation to RS and progression to symptomatic disease according to NCI Working Group guidelines are distinct events in CLL. Accordingly, neither IGHV4-39 usage nor stereotypic HCDR3 affected the risk of CLL progression occurring without transformation to RS. IGHV4-39 usage and stereotypic HCDR3 may be appropriate biological markers for RS prediction since: these markers predict RS in a fashion that is independent of other clinical and biological features; given the widespread use of IGHV sequencing for CLL prognostication, information on IGHV4-39 and stereotypic HCDR3 may be obtained at CLL diagnosis without additional testing; and importantly all CLL with concomitant IGHV4-39 usage and stereotypic HCDR3 ultimately transform to RS. A close monitoring and a careful biopsy policy may be of help for early recognition of RS transformation in patients carrying IGHV4-39 usage and stereotypic HCDR3.

Sign in / Sign up

Export Citation Format

Share Document