Gene Summary

Gene:IGL; immunoglobulin lambda locus
Aliases: IGL@, IGLC6
Summary:Immunoglobulins recognize foreign antigens and initiate immune responses such as phagocytosis and the complement system. Each immunoglobulin molecule consists of two identical heavy chains and two identical light chains. There are two classes of light chains, kappa and lambda. This region represents the germline organization of the lambda light chain locus. The locus includes V (variable), J (joining), and C (constant) segments. During B cell development, a recombination event at the DNA level joins a single V segment with a J segment; the C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random additional of nucleotides by terminal deoxynucleotidyltransferase, and by somatic hypermutation, which occurs during B cell maturation in the spleen and lymph nodes. Several V segments and three C segments are known to be incapable of encoding a protein and are considered pseudogenes. The locus also includes several non-immunoglobulin genes, many of which are pseudogenes or are predicted by automated computational analysis or homology to other species. [provided by RefSeq, Jul 2008]
Databases:HGNC, GeneCard, Gene
Protein:ig lambda-6 chain C region
Source:NCBIAccessed: 29 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Non-Hodgkin Lymphoma
  • Immunohistochemistry
  • Chromosome 14
  • Base Sequence
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain
  • Immunoglobulin Heavy Chains
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins
  • DNA-Binding Proteins
  • Chromosome 22
  • Gene Rearrangement, B-Lymphocyte, Light Chain
  • Trisomy
  • myc Genes
  • FISH
  • Immunoglobulins
  • Transcription Factors
  • Immunoglobulin Light Chains
  • Immunoglobulin kappa-Chains
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
  • Somatic Hypermutation, Immunoglobulin
  • B-Cell Lymphoma
  • Immunoglobulin lambda-Chains
  • Immunophenotyping
  • Restriction Mapping
  • B-Lymphocytes
  • Receptors, Antigen, B-Cell
  • Karyotyping
  • Adolescents
  • Cancer Gene Expression Regulation
  • Proto-Oncogene Proteins c-myc
  • Multiple Myeloma
  • Follicular Lymphoma
  • Molecular Sequence Data
  • Gene Rearrangement
  • Chromosome Aberrations
  • Chronic Lymphocytic Leukemia
  • Southern Blotting
  • Genes, Immunoglobulin
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IGL (cancer-related)

Barwick BG, Neri P, Bahlis NJ, et al.
Multiple myeloma immunoglobulin lambda translocations portend poor prognosis.
Nat Commun. 2019; 10(1):1911 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.

Nakayama S, Oda T, Minabe S, et al.
Primary Nonsecretory Plasma Cell Leukemia With Multiple Chromosomal Abnormalities: A Case Report.
Arch Iran Med. 2018; 21(1):41-43 [PubMed] Related Publications
Primary nonsecretory plasma cell leukemia (PCL) is an extremely rare type of multiple myeloma. Here, we report a case of nonsecretory PCL with no previous history of multiple myeloma. The case exhibited extremely low levels of serum immunoglobulin and light chain, no detectable serum M-protein or free light chain restriction, no urine BJP, and no cytoplasmic light chain expression in flow cytometry. In fluorescence in situ hybridization, tumor cells exhibited fusion genes for IgH/BCL1 and IgH/cMyc, disappearance of the p53 signal, and a split signal for IgK(2p11), but no split signal for IgL (22q11). Therefore, we diagnosed primary nonsecretory PCL with multiple chromosomal abnormalities.

Aukema SM, van Pel R, Nagel I, et al.
MYC expression and translocation analyses in low-grade and transformed follicular lymphoma.
Histopathology. 2017; 71(6):960-971 [PubMed] Related Publications
AIMS: Low-grade follicular lymphoma (FL) (grade 1/2, FL1/2) has an annual risk of transformation of ≈3%, which is associated with aberrations in CDKN2A/B, TP53, and MYC. As in diffuse large B-cell lymphoma, high MYC expression in transformed FL (tFL) might predict a MYC breakpoint.
METHODS AND RESULTS: We quantified MYC expression by immunohistochemistry and digital analysis in 41 paired biopsies from 20 patients with FL1/2 with subsequent transformation and in four isolated biopsies of tFL. As controls, 28 biopsies of FL1/2 without transformation (median follow-up of 105 months) and nine biopsies of FL3A/B were analysed. In the 20 FL1/2-tFL pairs, MYC expression was significantly higher in tFL than in the initial FL1/2 biopsies (median 54% versus 6%; 7% in FL3A, and 35% in FL3B). MYC breaks (MYC-R) were detected in eight of 21 (38%) tFLs analysed by fluorescence in-situ hybridization (FISH), with a median MYC score of 86%. In two of the analysed tFL cases, the translocation was already detected in antecedent FL1/2. MYC partners were immunoglobulin (IG) loci in three of eight cases (one IGL, one IGH, and one IGK) and non-IG in five of eight cases (two PAX5, one BCL6, and two unknown). Of the eight MYC-R+ cases, six were BCL2+/MYC+ double-hit, one was BCL2+/BCL6+/MYC+ triple-hit, and one was MYC+ single-hit. All three IG-MYC+ cases showed a MYC expression level of >85%, whereas the five cases with a non-IG MYC partner had a wider range of expression (median 68%, range 13-86%). Among the 13 MYC-R- tFLs, two groups with almost dichotomous MYC expression could be observed (three cases showed ≥90% MYC expression), suggesting alternative mechanisms of MYC activation.
CONCLUSIONS: we show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in ≈40% of the cases, which is markedly higher than in de novo DLBCL. MYC expression was uniformly high in cases with an IG-MYC translocation but much more heterogeneous and in part independent of the presence of a MYC break in non-IG-MYC and MYC-negative cases.

Akasaka T, Kishimori C, Fukutsuka K, et al.
The novel double-hit, t(8;22)(q24;q11)/MYC-IGL and t(14;15)(q32;q24)/IGH-BCL2A1, in diffuse large B-cell lymphoma.
Cancer Genet. 2017; 214-215:26-31 [PubMed] Related Publications
An 82-year-old woman presented with generalized lymphadenopathy and skin involvement. Lymph node biopsy revealed diffuse large B-cell lymphoma with a high proliferation index. G-banding and fluorescence in situ hybridization showed a hypertetraploid karyotype with two copies of t(8;22)(q24;q11), generating the fusion of MYC and the immunoglobulin λ chain gene (IGL), and two copies of the novel immunoglobulin heavy chain gene (IGH) translocation, t(14;15)(q32;q24). A long-distance inverse polymerase chain reaction (PCR) using nested primer combinations designed for each constant gene of IGH showed that Cγ4 was juxtaposed to the downstream sequence of the BCL2A1 (BCL2-related protein A1) gene through the Sγ4 switch region. As a result of t(14;15)(q32;q24), BCL2A1 and IGH Sγ4-Cγ4 were aligned in the same transcriptional orientation at a distance of 64 kb. Reverse transcriptase-mediated PCR showed high BCL2A1 mRNA levels in a lymphoma specimen. Since BCL2A1, mapped at 15q24.3 or 15q25.1, encodes a protein that is an anti-apoptotic member of the BCL2 protein family, we herein described the novel double-hit, t(8;22)(q24;q11)/MYC-IGL and t(14;15)(q32;q24)/IGH-BCL2A1, in which BCL2A1 is considered to play a role equivalent to that of BCL2 in the most frequent double-hit, MYC/BCL2.

Meyer JA, Zhou D, Mason CC, et al.
Genomic characterization of pediatric B-lymphoblastic lymphoma and B-lymphoblastic leukemia using formalin-fixed tissues.
Pediatr Blood Cancer. 2017; 64(7) [PubMed] Related Publications
BACKGROUND: Recurrent genomic changes in B-lymphoblastic leukemia (B-ALL) identified by genome-wide single-nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B-lymphoblastic lymphoma (B-LBL), is limited by the low incidence and lack of fresh tissue for genomic testing.
PROCEDURE: We used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin-fixed paraffin-embedded pediatric B-LBL (n = 23) and B-ALL (n = 55).
RESULTS: Similar to B-ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B-LBL cases. Eleven of 23 (48%) B-LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B-ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B-LBL, respectively, which was similar to the reported frequency in B-ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B-LBL cases, compared with only 1% in B-ALL samples. None of the B-LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B-ALL.
CONCLUSIONS: Our study demonstrates that the copy number profile of B-LBL is distinct from B-ALL, suggesting possible differences in pathogenesis between these closely related diseases.

Kurita D, Takeuchi K, Kobayashi S, et al.
A cyclin D1-negative mantle cell lymphoma with an IGL-CCND2 translocation that relapsed with blastoid morphology and aggressive clinical behavior.
Virchows Arch. 2016; 469(4):471-6 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is a B cell neoplasm characterized by cyclin D1 overexpression; its prognosis is poor, especially when it exhibits a blastoid morphology. Cyclin D1-negative MCL is rare, and its pathogenesis and progression remain unclear. Herein, we describe a cyclin D1-negative, cyclin D2-positive MCL with a CCND2 and immunoglobulin lambda light chain (IGL) translocation. The patient was initially diagnosed with cyclin D1-negative MCL and achieved complete remission via combination chemotherapy and autologous stem cell transplantation. After relapsing, he was diagnosed with a blastoid variant of MCL that showed lymphoid cells with dispersed chromatin and more mitotic figures and higher p53 expression compared with the initial MCL. Despite salvage therapies, the disease became refractory, and the patient died 28 months after initiating chemotherapy. This case demonstrates that blastoid morphology in cyclin D1-negative MCL with IGL-CCND2 translocation indicates progression to a more aggressive neoplasm, similar to cyclin D1-positive MCL.

Van Roosbroeck K, Ferreiro JF, Tousseyn T, et al.
Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies.
Genes Chromosomes Cancer. 2016; 55(5):428-41 [PubMed] Related Publications
The recurrent 9p24.1 aberrations in lymphoid malignancies potentially involving four cancer-related and druggable genes (JAK2, CD274/PDL1, PDCD1LG2/PDL2, and KDM4C/JMJD2Cl) are incompletely characterized. To gain more insight into the anatomy of these abnormalities, at first we studied 9p24.1 alterations in 18 leukemia/lymphoma cases using cytogenetic and molecular techniques. The aberrations comprised structural (nine cases) and numerical (nine cases) alterations. The former lesions were heterogeneous but shared a common breakpoint region of 200 kb downstream of JAK2. The rearrangements predominantly targeted the PDL locus. We have identified five potential partner genes of PDL1/2: PHACTR4 (1p34), N4BP2 (4p14), EEF1A1 (6q13), JAK2 (9p24.1), and IGL (22q11). Interestingly, the cryptic JAK2-PDL1 rearrangement was generated by a microdeletion spanning the 3'JAK2-5'PDL1 region. JAK2 was additionally involved in a cytogenetically cryptic IGH-mediated t(9;14)(p24.1;q32) found in two patients. This rare but likely underestimated rearrangement highlights the essential role of JAK2 in B-cell neoplasms. Cases with amplification of 9p24.1 were diagnosed as primary mediastinal B-cell lymphoma (five cases) and T-cell lymphoma (four cases). The smallest amplified 9p24.1 region was restricted to the JAK2-PDL1/2-RANBP6 interval. In the next step, we screened 200 cases of classical Hodgkin lymphoma by interphase FISH and identified PDL1/2 rearrangement (CIITA- and IGH-negative) in four cases (2%), what is a novel finding. Forty (25%) cases revealed high level amplification of 9p24.1, including four cases with a selective amplification of PDL1/2. Altogether, the majority of 9p24.1 rearrangements occurring in lymphoid malignancies seem to target the programmed death-1 ligands, what potentiates the therapeutic activity of PD-1 blockade in these tumors. © 2016 Wiley Periodicals, Inc.

Szablewski V, Ingen-Housz-Oro S, Baia M, et al.
Primary Cutaneous Follicle Center Lymphomas Expressing BCL2 Protein Frequently Harbor BCL2 Gene Break and May Present 1p36 Deletion: A Study of 20 Cases.
Am J Surg Pathol. 2016; 40(1):127-36 [PubMed] Related Publications
The classification of cutaneous follicular lymphoma (CFL) into primary cutaneous follicle center lymphoma (PCFCL) or secondary cutaneous follicular lymphoma (SCFL) is challenging. SCFL is suspected when tumor cells express BCL2 protein, reflecting a BCL2 translocation. However, BCL2 expression is difficult to assess in CFLs because of numerous BCL2+ reactive T cells. To investigate these issues and to further characterize PCFCL, we studied a series of 25 CFLs without any extracutaneous disease at diagnosis, selected on the basis of BCL2 protein expression using 2 BCL2 antibodies (clones 124 and E17) and BOB1/BCL2 double immunostaining. All cases were studied using interphase fluorescence in situ hybridization with BCL2, BCL6, IGH, IGK, IGL breakapart, IGH-BCL2 fusion, and 1p36/1q25 dual-color probes. Nineteen CFLs were BCL2 positive, and 6 were negative. After a medium follow-up of 24 (6 to 96) months, 5 cases were reclassified as SCFL and were excluded from a part of our analyses. Among BCL2+ PCFCLs, 60% (9/15) demonstrated a BCL2 break. BCL2-break-positive cases had a tendency to occur in the head and neck and showed the classical phenotype of nodal follicular lymphoma (CD10+, BCL6+, BCL2+, STMN+) compared with BCL2-break-negative PCFCLs. Del 1p36 was observed in 1 PCFCL. No significant clinical differences were observed between BCL2+ or BCL2- PCFCL. In conclusion, we show that a subset of PCFCLs harbor similar genetic alterations, as observed in nodal follicular lymphomas, including BCL2 breaks and 1p36 deletion. As BCL2 protein expression is usually associated with the presence of a BCL2 translocation, fluorescence in situ hybridization should be performed to confirm this hypothesis.

Ceccarelli M, Micheli L, D'Andrea G, et al.
Altered cerebellum development and impaired motor coordination in mice lacking the Btg1 gene: Involvement of cyclin D1.
Dev Biol. 2015; 408(1):109-25 [PubMed] Related Publications
Cerebellar granule neurons develop postnatally from cerebellar granule precursors (GCPs), which are located in the external granule layer (EGL) where they massively proliferate. Thereafter, GCPs become postmitotic, migrate inward to form the internal granule layer (IGL), further differentiate and form synapses with Purkinje cell dendrites. We previously showed that the Btg family gene, Tis21/Btg2, is required for normal GCP migration. Here we investigated the role in cerebellar development of the related gene, Btg1, which regulates stem cell quiescence in adult neurogenic niches, and is expressed in the cerebellum. Knockout of Btg1 in mice caused a major increase of the proliferation of the GCPs in the EGL, whose thickness increased, remaining hyperplastic even after postnatal day 14, when the EGL is normally reduced to a few GCP layers. This was accompanied by a slight decrease of differentiation and migration of the GCPs and increase of apoptosis. The GCPs of double Btg1/Tis21-null mice presented combined major defects of proliferation and migration outside the EGL, indicating that each gene plays unique and crucial roles in cerebellar development. Remarkably, these developmental defects lead to a permanent increase of the adult cerebellar volume in Btg1-null and double mutant mice, and to impairment in all mutants, including Tis21-null, of the cerebellum-dependent motor coordination. Gain- and loss-of-function strategies in a GCP cell line revealed that Btg1 regulates the proliferation of GCPs selectively through cyclin D1. Thus, Btg1 plays a critical role for cerebellar maturation and function.

Ambrosio MR, Rocca BJ, Ginori A, et al.
A look into the evolution of Epstein-Barr virus-induced lymphoproliferative disorders: a case study.
Am J Clin Pathol. 2015; 144(5):817-22 [PubMed] Related Publications
OBJECTIVES: Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (LPDs) are lymphoid proliferations arising as a result of the loss of an effective EBV-specific cytotoxic T-cell response. LPDs may occur for primary or acquired impairment of the immune system, as well as in some persons without documented immunodeficiency.
METHODS: In this article, we describe the case of a human immunodeficiency virus-positive patient affected by an EBV-LPD of the stomach who developed a nodal diffuse large B-cell lymphoma with complex morphologic and molecular features.
RESULTS: GeneScan analysis of the gastric specimen identified two different heavy-chain immunoglobulin gene (IGH) rearrangements characterized by a dominant peak of 285 base pairs (bp) in length and a smaller peak of 266 bp in length. In the lymph node sample, IGH evaluation also demonstrated two different peaks; however, the main peak corresponded to the minor peak detected in the EBV-LPD specimen at the diagnosis. In addition, a monoclonal immunoglobulin light chain gene (IGL) rearrangement was also found. We also demonstrated that the major peak in the stomach corresponded to the EBV-positive population observed in the histologic sections.
CONCLUSIONS: This case may provide additional insights to better understanding the "hit-and-run" role for EBV in lymphomagenesis. However, we could not exclude that our findings represent the co-occurrence of two unrelated B-cell neoplasms rather than a progression from an EBV-positive neoplasm to an EBV-negative one.

Copie-Bergman C, Cuillière-Dartigues P, Baia M, et al.
MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study.
Blood. 2015; 126(22):2466-74 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) with MYC rearrangement (MYC-R) carries an unfavorable outcome. We explored the prognostic value of the MYC translocation partner gene in a series of MYC-R de novo DLBCL patients enrolled in first-line prospective clinical trials (Groupe d'Etudes des Lymphomes de l'Adulte/Lymphoma Study Association) and treated with rituximab-anthracycline-based chemotherapy. A total of 774 DLBCL cases characterized for cell of origin by the Hans classifier were analyzed using fluorescence in situ hybridization with BCL2, BCL6, MYC, immunoglobulin (IG)K, and IGL break-apart and IGH/MYC, IGK/MYC, and IGL/MYC fusion probes. MYC-R was observed in 51/574 (8.9%) evaluable DLBCL cases. MYC-R cases were predominantly of the germinal center B-cell-like subtype 37/51 (74%) with no distinctive morphologic and phenotypic features. Nineteen cases were MYC single-hit and 32 cases were MYC double-hit (MYC plus BCL2 and/or BCL6) DLBCL. MYC translocation partner was an IG gene in 24 cases (MYC-IG) and a non-IG gene (MYC-non-IG) in 26 of 50 evaluable cases. Noteworthy, MYC-IG patients had shorter overall survival (OS) (P = .0002) compared with MYC-negative patients, whereas no survival difference was observed between MYC-non-IG and MYC-negative patients. In multivariate analyses, MYC-IG predicted poor progression-free survival (P = .0051) and OS (P = .0006) independently from the International Prognostic Index and the Hans classifier. In conclusion, we show in this prospective randomized trial that the adverse prognostic impact of MYC-R is correlated to the MYC-IG translocation partner gene in DLBCL patients treated with immunochemotherapy. These results may have an important impact on the clinical management of DLBCL patients with MYC-R who should be routinely characterized according to MYC partner gene. These trials are individually registered at www.clinicaltrials.gov as #NCT00144807, #NCT01087424, #NCT00169143, #NCT00144755, #NCT00140660, #NCT00140595, and #NCT00135499.

Ghorbian S, Jahanzad I, Javadi GR, Sakhinia E
Evaluation of IGK and IGL molecular gene rearrangements according to the BIOMED-2 protocols for clinical diagnosis of Hodgkin lymphoma.
Hematology. 2016; 21(3):133-7 [PubMed] Related Publications
BACKGROUND: Although the analysis of molecular clonality rearrangements of the immunoglobulin light chains (IGK and IGL) is an alternative approach for diagnosis of B cell non-Hodgkin lymphomas (NHLs) using BIOMED-2 protocols, NHLs have not been extensively confirmed for Hodgkin lymphoma (HL) cases. We evaluated BIOMED-2 protocols in HL cases, which have been suggested previously as gold standard method for molecular clonality analysis on formalin fixed, paraffin-embedded (FFPE) tissue in NHL patients.
METHODS: We recruited 50 consecutive FFPE tissues of HL samples to evaluate IGK and IGL clonality gene rearrangements using BIOMED-2 and Heteroduplex methods.
RESULTS: Our findings revealed a total of 94% (47/50) positive clonality, which consisted of 70% (35/50) for IGK and 44% (22/50) for IGL. In three cases, clonality was not detected in any of the immunoglobulin gene segments.
CONCLUSIONS: Analysis of clonality gene rearrangements in IGK and IGL genes using BIOMED-2 protocols could be implemented as a valuable method for improving clonality detection rate in HL cases and sensitivity (94%) and accuracy of HL diagnosis similar to that of the NHL samples will be increased.

Aricò A, Ferraresso S, Bresolin S, et al.
Array-based comparative genomic hybridization analysis reveals chromosomal copy number aberrations associated with clinical outcome in canine diffuse large B-cell lymphoma.
PLoS One. 2014; 9(11):e111817 [PubMed] Free Access to Full Article Related Publications
Canine Diffuse Large B-cell Lymphoma (cDLBCL) is an aggressive cancer with variable clinical response. Despite recent attempts by gene expression profiling to identify the dog as a potential animal model for human DLBCL, this tumor remains biologically heterogeneous with no prognostic biomarkers to predict prognosis. The aim of this work was to identify copy number aberrations (CNAs) by high-resolution array comparative genomic hybridization (aCGH) in 12 dogs with newly diagnosed DLBCL. In a subset of these dogs, the genetic profiles at the end of therapy and at relapse were also assessed. In primary DLBCLs, 90 different genomic imbalances were counted, consisting of 46 gains and 44 losses. Two gains in chr13 were significantly correlated with clinical stage. In addition, specific regions of gains and losses were significantly associated to duration of remission. In primary DLBCLs, individual variability was found, however 14 recurrent CNAs (>30%) were identified. Losses involving IGK, IGL and IGH were always found, and gains along the length of chr13 and chr31 were often observed (>41%). In these segments, MYC, LDHB, HSF1, KIT and PDGFRα are annotated. At the end of therapy, dogs in remission showed four new CNAs, whereas three new CNAs were observed in dogs at relapse compared with the previous profiles. One ex novo CNA, involving TCR, was present in dogs in remission after therapy, possibly induced by the autologous vaccine. Overall, aCGH identified small CNAs associated with outcome, which, along with future expression studies, may reveal target genes relevant to cDLBCL.

Watson CT, Steinberg KM, Graves TA, et al.
Sequencing of the human IG light chain loci from a hydatidiform mole BAC library reveals locus-specific signatures of genetic diversity.
Genes Immun. 2015 Jan-Feb; 16(1):24-34 [PubMed] Free Access to Full Article Related Publications
Germline variation at immunoglobulin (IG) loci is critical for pathogen-mediated immunity, but establishing complete haplotype sequences in these regions has been problematic because of complex sequence architecture and diploid source DNA. We sequenced BAC clones from the effectively haploid human hydatidiform mole cell line, CHM1htert, across the light chain IG loci, kappa (IGK) and lambda (IGL), creating single haplotype representations of these regions. The IGL haplotype generated here is 1.25 Mb of contiguous sequence, including four novel IGLV alleles, one novel IGLC allele, and an 11.9-kb insertion. The CH17 IGK haplotype consists of two 644 kb proximal and 466 kb distal contigs separated by a large gap of unknown size; these assemblies added 49 kb of unique sequence extending into this gap. Our analysis also resulted in the characterization of seven novel IGKV alleles and a 16.7-kb region exhibiting signatures of interlocus sequence exchange between distal and proximal IGKV gene clusters. Genetic diversity in IGK/IGL was compared with that of the IG heavy chain (IGH) locus within the same haploid genome, revealing threefold (IGK) and sixfold (IGL) higher diversity in the IGH locus, potentially associated with increased levels of segmental duplication and the telomeric location of IGH.

Abbas F, Yazbek SN, Shammaa D, et al.
Invivoscribe BIOMED-2 primer mixes in B-cell immunoglobulin gene rearrangement studies: experience of a molecular diagnostics laboratory in a major tertiary care center.
Genet Test Mol Biomarkers. 2014; 18(12):787-90 [PubMed] Related Publications
AIMS: To determine the frequency of positive reactions obtained using the Invivoscribe BIOMED-2 kit for B-cell gene rearrangement studies in leukemias and lymphomas.
MATERIALS AND METHODS: We reviewed the gel patterns for 192 samples tested, using the above-mentioned kit and matched the positive signal with the corresponding mix available in the assay kit.
RESULTS: 92.2% had immunoglobulin heavy-chain clonality, of which 74% were detected by the IgH VH-FR1+JH primer set, 75.5% by IgH VH-FR2+JH primer set, 65.1% by IgH VH-FR3+JH primer set, 26% by IgH DH+JH primer set, and 2.1% by IgH DH7+JH primer set. In addition, 55.7% had clonality in the kappa light chain, where 33.3% were positive by the IgK Vκ +Jκ primer set and 39.6% by IgK Vκ and INTR+Kde primer sets. Clonality in the lambda light chain of immunoglobulins was detected in 17.7% of specimens tested using the IgL Vλ +Jλ primer set.
CONCLUSION: All primer mixes provided by the assay were positive. Thus, the Invivoscribe BIOMED-2 B-cell gene rearrangement kit is very reliable in adequately covering all targets represented by the master mixes. This assay is an integral part of the differential diagnosis of clonal populations of cells. Our report is the first in the literature that describes the full range of coverage of the BIOMED-2 primer mixes provided in this assay.

Li K, Johnson RL, Li S, et al.
Nodal involvement by marginal zone B-cell lymphoma harboring t(14;22)(q32;q11) involving immunoglobulin heavy chain and light chain lambda as the sole karyotypically recognizable abnormality in a patient with systemic lupus erythematosus.
Int J Clin Exp Pathol. 2014; 7(8):5221-31 [PubMed] Free Access to Full Article Related Publications
Recurrent non-random balanced chromosomal translocation, usually involving the immunoglobulin heavy chain (IgH) gene or an immunoglobulin light chain gene and a proto-oncogene, which results in the overexpression of the latter under the control of an enhancer or promoter of the former, is a hallmark of many types of non-Hodgkin lymphoma (NHL) of B-cell origin. However, translocations between IgH and the immunoglobulin (Ig) light chain lambda gene (IgL), namely, a t(14;22)(q32;q11), have rarely been described in B-cell NHL. Herein we report the first case of marginal zone B-cell lymphoma harboring a t(14;22)(q32;q11) as its sole genetic abnormality in a patient with a 12-year history of systemic lupus erythematosus (SLE). Other interesting findings of this case include: 1) the neoplastic B-cells lack expression of both surface and cytoplasmic Ig light chain as revealed by flow cytometry and 2) monoclonal rearrangement of Ig light chain kappa (IgK) only due to k-deleting element (kde) recombination event. This case illustrates the necessity of utilizing a multi-modality approach in the diagnosis of B-cell NHL.

Türkmen S, Binder A, Gerlach A, et al.
High prevalence of immunoglobulin light chain gene aberrations as revealed by FISH in multiple myeloma and MGUS.
Genes Chromosomes Cancer. 2014; 53(8):650-6 [PubMed] Related Publications
Multiple myeloma (MM) is a malignant B-cell neoplasm characterized by an uncontrolled proliferation of aberrant plasma cells in the bone marrow. Chromosome aberrations in MM are complex and represent a hallmark of the disease, involving many chromosomes that are altered both numerically and structurally. Nearly half of the cases are nonhyperdiploid and show IGH translocations with the following partner genes: CCND1, FGFR3 and MMSET, MAF, MAFB, and CCND3. The remaining 50% are grouped into a hyperdiploid group that is characterized by multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. In this study, we analyzed the immunoglobulin light chain kappa (IGK, 2p12) and lambda (IGL, 22q11) loci in 150 cases, mostly with MM but in a few cases monoclonal gammopathy of undetermined significance (MGUS), without IGH translocations. We identified aberrations in 27% (= 40 patients) including rearrangements (12%), gains (12%), and deletions (4.6%). In 6 of 18 patients with IGK or/and IGL rearrangements, we detected a MYC rearrangement which suggests that MYC is the translocation partner in the majority of these cases.

Affer M, Chesi M, Chen WG, et al.
Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma.
Leukemia. 2014; 28(8):1725-1735 [PubMed] Free Access to Full Article Related Publications
MYC locus rearrangements-often complex combinations of translocations, insertions, deletions and inversions-in multiple myeloma (MM) were thought to be a late progression event, which often did not involve immunoglobulin genes. Yet, germinal center activation of MYC expression has been reported to cause progression to MM in an MGUS (monoclonal gammopathy of undetermined significance)-prone mouse strain. Although previously detected in 16% of MM, we find MYC rearrangements in nearly 50% of MM, including smoldering MM, and they are heterogeneous in some cases. Rearrangements reposition MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g., IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1). MYC rearrangements are associated with a significant increase of MYC expression that is monoallelic, but MM tumors lacking a rearrangement have biallelic MYC expression at significantly higher levels than in MGUS. We also have shown that germinal center activation of MYC does not cause MM in a mouse strain that rarely develops spontaneous MGUS. It appears that increased MYC expression at the MGUS/MM transition usually is biallelic, but sometimes can be monoallelic if there is an MYC rearrangement. Our data suggest that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.

Dittmer DP
Not like a wrecking ball: EBV fine-tunes MYC lymphomagenesis.
Blood. 2014; 123(4):460-1 [PubMed] Free Access to Full Article Related Publications
In this issue of Blood, Fish et al uncover how Epstein-Barr virus (EBV) enhances MYC-driven B-cell lymphoma by crossing EBV Em-EBV latent membrane protein 2A (LMP2A) transgenic mice with immunoglobulin-l (Igl)-MYC transgenic mice.

Rouhigharabaei L, Ferreiro JF, Put N, et al.
BMI1, the polycomb-group gene, is recurrently targeted by genomic rearrangements in progressive B-cell leukemia/lymphoma.
Genes Chromosomes Cancer. 2013; 52(10):928-44 [PubMed] Related Publications
BMI1, a Polycomb-group gene located at 10p12.2, is implicated in the pathogenesis of a variety of tumors. However, the genetic molecular mechanisms underlying its aberrant expression in cancer cells remain largely unknown. In this study, we show that BMI1 is recurrently targeted by chromosomal aberrations in B-cell leukemia/lymphoma. We identified a novel t(10;14)(p12;q32)/IGH-BMI1 rearrangement and its IGL variant in six cases of chronic lymphocytic leukemia (CLL) and found that these aberrations were consistently acquired at time of disease progression and high grade transformation of leukemia (Richter syndrome). The IG-BMI1 translocations were not associated with any particular molecular subtype of CLL and the leukemias were negative for common mutations of NOTCH1 and TP53, known to increase a risk of progression and transformation in CLL. In addition, using FISH and SNP array analysis, we identified a wide range of BMI1-involving 10p12 lesions in 17 cases of mantle cell lymphoma (MCL). These aberrations included various balanced and unbalanced structural abnormalities and very frequently but not exclusively, were associated with gain of the BMI1 locus and loss of the 10p terminal sequences. These findings point to genomic instability at the 10p region in MCL which likely promotes rearrangements and deregulation of BMI1. Our findings are in line with previously published observations correlating overexpression of BMI1 with tumor progression and chemoresistance. In summary, our study provides new insights into genetic molecular mechanisms underlying aberrant expression of BMI1 in lymphoma and documents its contribution in the pathogenesis of Richter syndrome and MCL.

Mraz M, Stano Kozubik K, Plevova K, et al.
The origin of deletion 22q11 in chronic lymphocytic leukemia is related to the rearrangement of immunoglobulin lambda light chain locus.
Leuk Res. 2013; 37(7):802-8 [PubMed] Related Publications
The technology of array comparative genomic hybridization (array-CGH/aCGH) enabled the identification of novel genomic aberrations in chronic lymphocytic leukemia (CLL) including the monoallelic and biallelic deletions affecting 22q11 locus. In contrast to previous publications, we hypothesized that the described 22q11 deletions are a consequence of the rearrangement of immunoglobulin lambda light chain locus (IGL) segments surrounding several protein-coding genes located in this region. Indeed, using array-CGH and PCR analysis we show that all deletions (n=7) affecting the 22q11 locus in our cohort (n=40) are based on the physiological mechanism of IGL rearrangement. This demonstrates that this loss of genetic material is likely not pathogenic and in fact is merely a marker of IGL rearrangement.

Salaverria I, Royo C, Carvajal-Cuenca A, et al.
CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma.
Blood. 2013; 121(8):1394-402 [PubMed] Free Access to Full Article Related Publications
Cyclin D1(-) mantle cell lymphomas (MCLs) are not well characterized, in part because of the difficulties in their recognition. SOX11 has been identified recently as a reliable biomarker of MCL that is also expressed in the cyclin D1(-) variant. We investigated 40 lymphomas with MCL morphology and immunophenotype that were negative for cyclin D1 expression/t(11;14)(q13;q32) but positive for SOX11. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and poor outcome (5-year overall survival, 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18 of 22, in particular with light chains (10 IGK@ and 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2, or CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1(-) SOX11(+) MCL patients analyzed by copy number arrays were similar to the conventional cyclin D1/SOX11 MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome for the patients. This comprehensive characterization of a large series of cyclin D1(-) MCL patients indicates that these tumors are clinically and biologically similar to the conventional cyclin D1(+) MCL and provides a basis for the proper identification and clinical management of these patients.

Papale F, Cafiero G, Grimaldi A, et al.
Galectin-3 expression in thyroid fine needle cytology (t-FNAC) uncertain cases: validation of molecular markers and technology innovation.
J Cell Physiol. 2013; 228(5):968-74 [PubMed] Related Publications
Thyroid cancer is not very common, accounting for 1-2% of all cancers, with a population incidence of about 0.004%. Currently, the ability to discriminate between follicular adenoma and carcinoma represents the major challenge in preclinical diagnosis of thyroid proliferative lesions. Better discrimination between the two would help avoid unnecessary thyroidectomy and save valuable resources. Over the years, galectin-3 (Gal-3) has been proposed as a diagnostic marker with varied success. In this paper, we used Environmental Scanning Electron Microscopy Immunogold Labelling (ESEM-IGL) to investigate the expression of Gal-3 on Thin-Prep fine needle aspiration cytology (FNAC). We optimized the ESEM-IGL method on thyroid cell lines (RO-82 and FTC-133) comparing our membrane Gal-3 labeling data with Western blot. We evaluated 183 thyroid FNAC from Italian patients with a uncertain pre-surgical diagnosis. ESEM-IGL method marker sensitivity is 71.2%, while specificity is 53.3% and diagnostic efficacy is 61.2%. Our results confirmed that Gal-3 expression is associated with situations of hypertrophy and/or cellular hyperproliferation, pathophysiological situations common both to adenomas and to thyroid carcinomas. The innovation of thyroid FNAC Thin-Prep ESEM-IGL shows the levels of Gal-3 immunolabeling clearly, even through the individual cells of a thyroid nodule. However, Gal-3 alone, as a molecular marker of thyroid cancer, can still have a limited application in pre-surgery diagnosis.

Onozawa M, Aplan PD
Illegitimate V(D)J recombination involving nonantigen receptor loci in lymphoid malignancy.
Genes Chromosomes Cancer. 2012; 51(6):525-35 [PubMed] Free Access to Full Article Related Publications
V(D)J recombination of antigen receptor loci (IGH, IGK, IGL, TCRA, TCRB, TCRG, and TCRD) is an essential mechanism that confers enormous diversity to the mammalian immune system. However, there are now at least six examples of intrachromosomal interstitial deletions caused by aberrant V(D)J recombination between nonantigen receptor loci; five of out these six are associated with lymphoid malignancy. The SIL-SCL fusion and deletions of CDKN2A, IKZF1, Notch1, and Bcl11b are all associated with lymphoid malignancy. These interstitial deletions seem to be species specific, as the deletions seen in mice are not seen in humans; the converse is true as well. Nucleotide sequence analysis of these rearrangements reveals the hallmarks of V(D)J recombination, including site specificity near cryptic heptamer signal sequences, exonucleolytic "nibbling" at the junction site, and nontemplated "N"-region nucleotide insertion at the junction site. Two of these interstitial deletions (murine Notch1 and Bcl11b deletions) have been detected, at low frequency, in tissues from healthy mice with no evidence of malignancy, similar to the finding of chromosomal translocations in the peripheral blood or tonsils of healthy individuals. The contention that these are mediated via V(D)J recombination is strengthened by in vivo assays using extrachromosomal substrates, and chromatin immunoprecipitation-sequence analysis which shows Rag2 binding at the sites of rearrangement. Although the efficiency of these "illegitimate" recombination events is several orders of magnitude less than that at bona fide antigen receptor loci, the consequence of such deletions, namely activation of proto-oncogenes or deletion of tumor suppressor genes, is devastating, and a major cause for lymphoid malignancy.

Tomita N
BCL2 and MYC dual-hit lymphoma/leukemia.
J Clin Exp Hematop. 2011; 51(1):7-12 [PubMed] Related Publications
Translocation of the BCL2 gene on the chromosome band 18q21.3 results in consistent expression of the Bcl2 protein, an apoptosis inhibitor. BCL2 usually translocates to the immunoglobulin (IG) heavy chain (IGH) gene as t(14;18)(q32;q21.3) and rarely to IG light chain (IGK, IGL) loci as t(2;18)(p11;q21.3) or t(18;22)(q21.3;q11). The t(14;18) translocation is observed in 70-95% of follicular lymphoma cases and 20-30% of diffuse large B-cell lymphoma (DLBCL) cases. The MYC gene on chromosome band 8q24 acts as an accelerator of cell proliferation. MYC translocates to 14q32/IGH as t(8;14)(q24;q32) or less commonly to 2p11/IGK as t(2;8)(p11;q24) or 22q11/IGL as t(8;22)(q24;q11). The 8q24/MYC translocation is detected in nearly all Burkitt lymphoma (BL) and up to 10% of DLBCL cases. Both translocations rarely occur in an identical cell and this lymphoid malignancy is termed BCL2 and MYC dual-hit lymphoma/leukemia (DHL). The pathological diagnosis in most cases of DHL with BCL2-IG and MYC-IG translocation is B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, although DLBCL is most common in DHL with BCL2-IG and MYC-nonIG translocation. The frequency of DHL with BCL2 and MYC translocation is estimated at around 2% of all B-cell malignancies. The condition is characterized by elevated serum lactate dehydrogenase levels, the presence of B symptoms, bone marrow involvement, advanced disease stage, extranodal involvement, and central nervous system (CNS) involvement at presentation or disease progression. Despite treatment strategies including CNS-targeted therapy, the prognosis for DHL is extremely poor. In this review, the current knowledge of the clinicopathological status of DHL is summarized and discussed.

Shiller SM, Zieske A, Holmes H, et al.
CD5-positive, cyclinD1-negative mantle cell lymphoma with a translocation involving the CCND2 gene and the IGL locus.
Cancer Genet. 2011; 204(3):162-4 [PubMed] Related Publications
Distinguishing mantle cell lymphoma (MCL), from low-grade B-cell lymphoma is important because MCL is clinically more aggressive and is treated differently. Though most MCL overexpress cyclinD1 (CCND1) and have a t(11;14)(q13;q32), MCL that are negative for CCND1 exist. Some have translocations involving cyclinD2 (CCND2) and either the immunoglobulin heavy chain or kappa light chain locus. We present a CD5-positive, CCND1-negative B-cell lymphoma with a novel translocation involving CCND2 and the immunoglobulin lambda (IGL) gene. A 64-year-old male underwent resection of a polypoid mass of the ileum. Histology showed atypical, medium-sized lymphoid cells positive for CD20, CD5, CD43, and CCND2 by immunohistochemistry, and negative for CCND1, CCND3, and p27. Fluorescence in situ hybridization was negative for CCND1 abnormalities, but demonstrated a CCND2/IGL fusion. Clinical workup revealed stage IV disease. Current diagnostic criteria are insufficient for subclassifying this case, highlighting the need for additional studies on CCND2-translocated B-cell lymphomas to guide therapy appropriately.

Mansmann U, Jurinovic V
Biological feature validation of estimated gene interaction networks from microarray data: a case study on MYC in lymphomas.
Brief Bioinform. 2011; 12(3):230-44 [PubMed] Related Publications
Gene expression is a dynamic process where thousands of components interact dynamically in a complex way. A major goal in systems biology/medicine is to reconstruct the network of components from microarray data. Here, we address two key aspects of network reconstruction: (i) ergodicity supports the interpretation of the measured data as time averages and (ii) confounding is an important aspect of network reconstruction. To elucidate these aspects, we explore a data set of 214 lymphoma patients with translocated or normal MYC gene. MYC (c-Myc) translocations to immunoglobulin heavy-chain (IGH@) or light-chain (IGK@, IGL@) loci lead to c-Myc overexpression and are widely believed to be the crucial initiating oncogenic events. There is a rich body of knowledge on the biological implications of the different translocations. In the context of these data, the article reflects the relationship between the biological knowledge and the results of formal statistical estimates of gene interaction networks. The article identifies key steps to provide a trustworthy biological feature validation: (i) analysing a medium-sized network as a subnet of a more extensive environment to avoid bias by confounding, (ii) the use of external data to demonstrate the stability and reproducibility of the derived structures, (iii) a systematic literature review on the relevant issue, (iv) use of structured knowledge from databases to support the derived findings and (v) a strategy for biological experiments derived from the findings in steps (i-iv).

Liang X, Jones A, Giller RH, et al.
Primary high-grade B-cell lymphoma of the breast with concurrent IGH-BCL2 and MYC-IGL translocations in an adolescent patient.
Pediatr Dev Pathol. 2011 Sep-Oct; 14(5):402-6 [PubMed] Related Publications
BCL2 and MYC are oncogenes often deregulated in lymphomas. Concurrent IGH-BCL2 and MYC translocations result in a highly aggressive behavior of these tumors. Both primary breast lymphoma and lymphoma with concurrent BCL2-IGH and MYC translocations are rare and are primarily seen in adult patients. As a result of limited clinician experience and the condition's rarity, it poses a great challenge to pediatric pathologists and oncologists in terms of making an accurate diagnosis and choosing better treatment regimens. In this article, we report a case of an adolescent patient who presented with high-grade breast lymphoma with concurrent BCL2-IGH and MYC-IGL translocations, and we review the clinical, pathological, and genetic features; management strategies; and outcomes associated with this unusual neoplasm.

Yan B, Tan SY, Yau EX, et al.
EBV-positive plasmacytoma of the submandibular gland--report of a rare case with molecular genetic characterization.
Head Neck Pathol. 2011; 5(4):389-94 [PubMed] Free Access to Full Article Related Publications
Plasmacytomas are differentiated plasma cell tumors that present as a mass lesion in osseous or extraosseous sites. Although the most common site for extramedullary plasmacytomas (EMP) is in the upper respiratory tract, plasmacytomas initially presenting as salivary gland masses are very uncommon. We describe a case of an EBV-positive plasmacytoma presenting as a 7.7 cm submandibular mass in an elderly immunocompetent man which displayed an abundance of "naked nuclei" on fine needle aspiration cytology. The tumor showed lambda light chain restriction and positive expression for CD38, MUM1 and EBER. Subsequent investigation for myeloma revealed absence of M-protein and end-organ damage, except for a lytic lesion in the radial bone. An extensive fluorescent in situ hybridization analysis showed the tumor to be negative for the t(4;14) FGFR3/IGH translocation as well as translocations involving the IGH, IGL, IGK, CCND1, BCL2, BCL6 and C-MYC genes. KRAS genetic analysis did not reveal any mutations of codons 12, 13 and 61.

Janegová A, Janega P, Ilencíková D, Babál P
Burkitt lymphoma with unusual granulomatous reaction. A case report.
Cesk Patol. 2011; 47(1):19-22 [PubMed] Related Publications
Formation of epithelioid histiocytic cell granulomas has been described in the post in various neoplasms, hematologic malignancies included. Among lymphoproliferative disorders such changes are commonly found in Hodgkin lymphoma and T-cell non-Hodgkin lymphomas (NHL), but are rarely described in B-NHL, like Burkitt lymphoma. This report presents a case of sporadic Burkitt lymphoma accompanied by a sarcoid-like reaction without any clinical, laboratory or histological evidence of microorganisms nor sarcoidosis. Using in situ hybridization and polymerase chain reaction the presence of the Epstein-Barr virus (EBV) was detected in the analyzed lymphoma cells. EBV demonstrated latency I phenotype as defined by the lack of immunohistochemical positivity of latent membrane protein 1 (LMP1). Cytogenetic investigation using fluorescence in situ hybridization uncovered c-MYC mutation and provided indirect indication for the MYC/IgL fusion gene. The lack of EBV positivity in histiocytes indicated the reactive character of the granulomatous reaction in relation to the neoplasm. The role of the granulomatous reaction in the biology and prognosis of Burkitt lymphoma and the function of EBV infection in its development remain to be established.

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