IGH

Gene Summary

Gene:IGH; immunoglobulin heavy locus
Aliases: IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1
Location:14q32.33
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. This region represents the germline organization of the heavy chain locus. The locus includes V (variable), D (diversity), J (joining), and C (constant) segments. During B cell development, a recombination event at the DNA level joins a single D segment with a J segment; this partially rearranged D-J gene is then joined to a V segment. The rearranged V-D-J is then transcribed with the IGHM constant region; this transcript encodes a mu heavy chain. Later in development B cells generate V-D-J-Cmu-Cdelta pre-messenger RNA, which is alternatively spliced to encode either a mu or a delta heavy chain. Mature B cells in the lymph nodes undergo switch recombination, so that the V-D-J gene is brought in proximity to one of the IGHG, IGHA, or IGHE genes and each cell expresses either the gamma, alpha, or epsilon heavy chain. 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. Due to polymorphism, the numbers of functional V, J, and D genes differ among individuals and some V, D, J, and C segments may be pseudogenes. [provided by RefSeq, Oct 2013]
Databases:OMIM, HGNC, GeneCard, Gene
Source:NCBIAccessed: 21 August, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 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.

Tag cloud generated 21 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (13)

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

Entity Topic PubMed Papers
Lymphoma, Mantle-Cellt(11;14)(q13;q32) in Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is characterised by a t(11;14)(q13;q32) translocation. This juxtaposes the CCND1 (bcl-1) locus to the immunoglobulin (IgH) gene sequences and leads to deregulation of cyclin D1. See Espinet B, et al, 1999 and Stamatopoulos K, et al, 1999.
View Publications396
Multiple MyelomaIGH and Multiple Myeloma View Publications268
Acute Lymphocytic Leukaemia (ALL)IGH and Acute Lymphocytic Leukaemia View Publications229
Chronic Lymphocytic LeukemiaIGH and Chronic Lymphocytic Leukemia View Publications156
MALT LymphomaIGH and MALT Lymphoma View Publications124
Lymphoma, Mantle-CellIGH and Mantle-Cell Lymphoma
In a GWAS study Bea et al (2013) reported IGHV mutations in 41% (12/29) of MTC cases.
View Publications63
Lymphomat(6;14)(p25,q32) in Lymphomas
This translocation is seen in some B-cell non Hodgkin lymphomas, particular in diffuse large B-cell lymphoma.
View Publications37
Waldenstrom's MacroglobulinemiaIGH and Waldenstrom's Macroglobulinemia View Publications22
-IGH and Splenic Neoplasms View Publications16
Non-Hodgkin Lymphomat(1;14)(q21;q32) and MUC1 Overexpression in NHL
Dyomin et al (2000) and Gilles et al (2000) reported that MUC1 is activated in Non-Hodgkin's lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphomas.
View Publications12
Multiple Myelomat(6;14)(p25;q32) in Myeloma
This translocation juxtaposes the IgH locus to the IRF4 gene resulting in overexpressed of IRF4, which is thought to contribute to tumorigenesis in Myeloma.
View Publications11
-t(11;14)(q23;q32) IGH-DDX6 Translocations in Hematologic Cancers View Publications1
Non-Hodgkin Lymphomat(1;14)(q21;q32) BCL9/IGH

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

Latest Publications: IGH (cancer-related)

Berget E, Molven A, Løkeland T, et al.
IGHV gene usage and mutational status in follicular lymphoma: Correlations with prognosis and patient age.
Leuk Res. 2015; 39(7):702-8 [PubMed] Related Publications
Follicular lymphoma (FL) is a heterogeneous disease with some patients developing progressively or transformed disease early, whereas others follow an indolent clinical course. We evaluated the prognostic value of immunoglobulin heavy chain variable (IGHV) gene usage and mutational status in FL patients. One hundred and four IGH sequences were obtained in tumour samples from 99 patients. The IGHV3 subgroup had the highest usage frequency (57.7%) with IGHV3-23 being the most common sequence. Patients with the IGHV5 subgroup or IGHV sequences from more than one subgroup had significantly less favourable prognosis with an estimated 5-year survival of 62.5 and 50.0%, respectively, as compared with a 5-year survival of 95.1% for patients with other IGHV subgroups (P=0.013 and P<0.001, log-rank). The poor survival associated with IGHV5 or >1 IGHV subgroup usage was an independent prognostic factor in Cox multivariate analysis (P=0.005). IGHV genes were unmutated showing >98% homology in 15.2% of cases. Contrasting the situation in chronic lymphocytic leukaemia (CLL), the presence of unmutated sequences did not yield prognostic information, although unmutated sequences were associated with age at diagnosis >60 years (P=0.022, Fisher's exact). In conclusion, our results indicate that analysis of IGHV gene usage might aid in predicting prognosis for FL patients.

He H, Fu W, Jiang H, et al.
The clinical characteristics and prognosis of IGH deletion in multiple myeloma.
Leuk Res. 2015; 39(5):515-9 [PubMed] Related Publications
OBJECTIVE: To analyze the frequency, clinical characteristics, and prognosis of IGH deletion in multiple myeloma (MM).
METHODS: A total of 310 consecutive patients with multiple myeloma were analyzed. Among them 251 patients were newly diagnosed and 59 patients were previously treated, fluorescence in situ hybridization (FISH) with IGH break apart probes were done for each case. Patterns of IGH deletion, response rate, overall survival, and progression free survival were analyzed.
RESULTS: Several patterns of IGH deletion were identified, including monoallelic deletion of whole locus of IGH, monoallelic deletion of 3' IGH, monoallelic deletion of 5' IGH, biallelic deletion of 3' IGH deletion, and complicated deletions with various types. The incidence rate of IGH deletion was 22.7% (57/251) in newly diagnosed patients and 27.2% (16/59) in previously treated patients, no significant difference was found between the two groups (p=0.375). IGH deletion was associated with κ light chain M component (p<0.001), 13q deletion (p=0.006), and absence of t(4; 14)(p=0.033). In the cases with 13q deletion, the frequency of IGH deletion is 3.5% (1/28) in patients with t(4;14) and 40.5% (32/79) in patients without t(4;14), significant difference was found (p=0.006). We further analyzed the response rates of patients with IGH deletion who received a uniform induction regimen of PAD composing of bortezomib, epirubicin, and dexamethasone. Overall response rate (ORR) in patients with IGH deletion was better than that in patients without IGH deletion (87.5 vs. 73.6%, p<0.001), while no significant difference was found in survival analysis, either OS or PFS (p=0.158 and p=0.177, respectively).
CONCLUSION: IGH deletion is frequent in multiple myeloma, the incidence rate was higher in patients with 13q deletion and without t(4;14). Patients with IGH deletion had better ORR to PAD induction therapy, while it has no influence on the prognosis of multiple myeloma.

Blachly JS, Ruppert AS, Zhao W, et al.
Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia.
Proc Natl Acad Sci U S A. 2015; 112(14):4322-7 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
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 × 10(12)) 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.

Hansen MC, Nyvold CG, Roug AS, et al.
Nature and nurture: a case of transcending haematological pre-malignancies in a pair of monozygotic twins adding possible clues on the pathogenesis of B-cell proliferations.
Br J Haematol. 2015; 169(3):391-400 [PubMed] Related Publications
We describe a comprehensive molecular analysis of a pair of monozygotic twins, who came to our attention when one experienced amaurosis fugax and was diagnosed with JAK2+ polycythaemia vera. He (Twin A) was also found to have an asymptomatic B-cell chronic lymphocytic leukaemia (B-CLL). Although JAK2-, Twin B was subsequently shown to have a benign monoclonal B-cell lymphocytosis (MBL). Flow cytometric and molecular analyses of the B-cell compartments revealed different immunoglobulin light and heavy chain usage in each twin. We hypothesized that whole exome sequencing could help delineating the pattern of germline B-cell disorder susceptibility and reveal somatic mutations potentially contributing to the differential patterns of pre-malignancy. Comparing bone marrow cells and T cells and employing in-house engineered integrative analysis, we found aberrations in Twin A consistent with a myeloid neoplasm, i.e. in TET2, RUNX1, PLCB1 and ELF4. Employing the method for detecting high-ranking variants by extensive annotation and relevance scoring, we also identified shared germline variants in genes of proteins interacting with B-cell receptor signalling mediators and the WNT-pathway, including IRF8, PTPRO, BCL9L, SIT1 and SIRPB1, all with possible implications in B-cell proliferation. Similar patterns of IGHV-gene usage to those demonstrated here have been observed in inherited acute lymphoblastic leukaemia. Collectively, these findings may help in facilitating identification of putative master gene(s) involved in B-cell proliferations in general and MBL and B-CLL in particular.

Marzec P, Armenise C, Pérot G, et al.
Nuclear-receptor-mediated telomere insertion leads to genome instability in ALT cancers.
Cell. 2015; 160(5):913-27 [PubMed] Related Publications
The breakage-fusion-bridge cycle is a classical mechanism of telomere-driven genome instability in which dysfunctional telomeres are fused to other chromosomal extremities, creating dicentric chromosomes that eventually break at mitosis. Here, we uncover a distinct pathway of telomere-driven genome instability, specifically occurring in cells that maintain telomeres with the alternative lengthening of telomeres mechanism. We show that, in these cells, telomeric DNA is added to multiple discrete sites throughout the genome, corresponding to regions regulated by NR2C/F transcription factors. These proteins drive local telomere DNA addition by recruiting telomeric chromatin. This mechanism, which we name targeted telomere insertion (TTI), generates potential common fragile sites that destabilize the genome. We propose that TTI driven by NR2C/F proteins contributes to the formation of complex karyotypes in ALT tumors.

Uccini S, Al-Jadiry MF, Scarpino S, et al.
Epstein-Barr virus-positive diffuse large B-cell lymphoma in children: a disease reminiscent of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly.
Hum Pathol. 2015; 46(5):716-24 [PubMed] Related Publications
Pediatric Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare disease in nonimmunocompromised hosts. In a review of 231 cases of malignant lymphoma (87 Hodgkin lymphoma and 144 non-Hodgkin lymphoma) occurring in Iraqi children, 7 cases (5% of NHLs) were classified as EBV+ DLBCL. Six children presented with nodal disease, and 1 presented with extranodal localization (bone). In all cases, the disease was at an advanced clinical stage (III/IV). Evidence of immunodeficiency (Evans syndrome and selective IgA deficiency) was observed in a single case. Two cases were "monomorphic" with immunoblastic histology, and 5 cases were "polymorphic" with histologic aspects reminiscent of nodular lymphocyte-predominant Hodgkin lymphoma (2 cases) and of CD30+ classical Hodgkin lymphoma (3 cases). In all cases, tumor cells were EBV infected (EBER+/LMP-1+), were medium-large B-cells (CD20+/CD79a+/PAX-5+/BOB-1+/OCT-2+) of non-germinal center (non-GC) origin (CD10-/MUM-1+), and had high proliferative activity (50%-70%). Chromosomal translocations involving BCL2, MYC, and IGH genes were not observed. IGH monoclonality could be demonstrated in 3 of 3 investigated cases. Six cases of EBV-negative DLBCL (4% of NHL) were present in the same series. All had monomorphic histology with centroblastic/immunoblastic morphology; 3 cases were of GC type and 3 of non-GC type. Our findings indicate that in Iraq, DLBCLs are 9% of NHLs. Moreover, 2 different types of the disease do exist; the EBV-positive cases, with strong histologic and immunohistochemical resemblance with EBV+ DLBCL of the elderly, and the EBV-negative cases, which are similar to the pediatric DLBCL usually observed in Western populations.

Kopparapu PK, Miranda C, Fogelstrand L, et al.
MCPH1 maintains long-term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia.
FEBS J. 2015; 282(10):1939-52 [PubMed] Related Publications
The microcephalin gene (MCPH1) [also known as inhibitor of human telomerase reverse transcriptase (hTERT) expression] is a tumor suppressor gene that is functionally involved in the DNA damage response. Angiopoietin 2 (ANGPT2) is a crucial factor regulating tumor angiopoiesis. Deregulation of angiogenesis is one of the hallmarks of many cancers, including chronic lymphocytic leukemia (CLL). In CLL, ANGPT2 is a well-studied potential prognostic marker. As MCPH1 overlaps with the ANGPT2 transcription unit on the same chromosome but in the opposite orientation, we wanted to study the functional role of MCPH1 in regulation of ANGPT2 in CLL. The mRNA expression levels of MCPH1 and ANGPT2, including the MCPH1 target gene hTERT, showed significant differences between two prognostic groups, i.e. IGHV-mutated and IGHV-unmutated (P = 0.007 for MCPH1, P = 0.0002 for ANGPT2, and P = 0.00001 for hTERT), in which the expression level of MCPH1 was inversely correlated with the expression levels of hTERT and ANGPT2. Downregulation of MCPH1 resulted in upregulation of ANGPT2, accompanied by loss of its promoter methylation. Using chromatin immunoprecipitation and coimmunoprecipitation assays, we found that MCPH1 binds to the ANGPT2 promoter and recruits DNA methyltransferases, thereby silencing ANGPT2. Thus, our data suggest a novel function for MCPH1 in regulating and maintaining ANGPT2 silencing in CLL through regulation of promoter DNA methylation.

Baliakas P, Agathangelidis A, Hadzidimitriou A, et al.
Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations.
Blood. 2015; 125(5):856-9 [PubMed] Article available free on PMC after 29/01/2016 Related Publications
An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.

Till KJ, Pettitt AR, Slupsky JR
Expression of functional sphingosine-1 phosphate receptor-1 is reduced by B cell receptor signaling and increased by inhibition of PI3 kinase δ but not SYK or BTK in chronic lymphocytic leukemia cells.
J Immunol. 2015; 194(5):2439-46 [PubMed] Article available free on PMC after 29/01/2016 Related Publications
BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton's tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechanisms underlying this phenomenon are incompletely understood. In this study, we showed that the egress receptor, sphingosine-1-phosphate (S1P) receptor 1 (S1PR1), was expressed at low levels in normal germinal centers and CLL lymph nodes in vivo but became upregulated on normal B cells and, to a variable and lesser extent, CLL cells following in vitro incubation in S1P-free medium. Spontaneous recovery of S1PR1 expression on normal B and CLL cells was prevented by BCR cross-linking, whereas treatment of CLL cells with idelalisib increased S1PR1 expression and migration toward S1P, the greatest increase occurring in cases with unmutated IgH V region genes. Intriguingly, ibrutinib and fostamatinib had no effect on S1PR1 expression or function. Conversely, chemokine-induced migration, which requires integrin activation and is essential for the entry of lymphocytes into lymph nodes as well as their retention, was blocked by ibrutinib and fostamatinib, but not idelalisib. In summary, our results suggest that different BCR signaling inhibitors redistribute CLL cells from lymph nodes into the blood through distinct mechanisms: idelalisib actively promotes egress by upregulating S1PR1, whereas fostamatinib and ibrutinib may reduce CLL cell entry and retention by suppressing chemokine-induced integrin activation.

Al-Kawaaz M, Mathew S, Liu Y, et al.
Cyclin D1-positive diffuse large B-cell lymphoma with IGH-CCND1 translocation and BCL6 rearrangement: a report of two cases.
Am J Clin Pathol. 2015; 143(2):288-99 [PubMed] Related Publications
OBJECTIVES: To demonstrate and confirm the existence of cyclin D1-positive diffuse large B-cell lymphoma (DLBCL) with IGH-CCND1 rearrangement and discuss the rationale of differentiating this entity from blastoid and pleomorphic variants of mantle cell lymphoma (MCL).
METHODS: Two cyclin D1-positive lymphomas with morphologic features of DLBCL and IGH-CCND1 translocations were characterized with respect to clinical features, as well as morphologic, immunophenotypic, cytogenetic, and molecular findings.
RESULTS: The large tumor cells were CD20+, CD5-, CD10-, BCL6+, MUM1+, and cyclin D1+ in both cases. SOX11 was negative. Epstein-Barr virus-encoded RNA in situ hybridization demonstrated diffuse positivity in case 1. BCL6 and IGH-CCND1 rearrangements were identified by fluorescence in situ hybridization in both cases. Specifically, the diagnosis of a relapsed DLBCL with acquisition of IGH-CCND1 was rendered for case 1, molecularly confirmed by the detection of identical monoclonal IGH rearrangements between the initial diagnostic DLBCL and relapse lymphoma.
CONCLUSIONS: Our study demonstrates convincingly that IGH-CCND1 rearrangement leading to cyclin D1 overexpression can occur in DLBCL and pose a potential diagnostic pitfall, requiring thorough knowledge of the clinicopathologic findings to allow accurate discrimination from a blastoid or pleomorphic MCL. The coexistence of IGH-CCND1 and IGH-BCL6 rearrangements suggest that BCL6 and cyclin D1 may cooperate in the pathogenesis of DLBCL.

Sata H, Shibayama H, Maeda I, et al.
Quantitative polymerase chain reaction analysis with allele-specific oligonucleotide primers for individual IgH VDJ regions to evaluate tumor burden in myeloma patients.
Exp Hematol. 2015; 43(5):374-381.e2 [PubMed] Related Publications
Quantitative polymerase chain reaction (PCR) with patient-specific, allele-specific oligonucleotide (ASO) primers for individual immunoglobulin H VDJ region (ASO-PCR) amplification was performed using several sources of clinical material, including mRNA from peripheral blood cells (PBMNCs), whole bone marrow cells (BMMNCs), and the CD20+ CD38- B-cell population in bone marrow, as well as cell-free DNA from the sera of patients with multiple myeloma (MM). We designed the ASO primers and produced sufficient PCR fragments to evaluate tumor burden in 20 of 30 bone marrow samples at diagnosis. Polymerase chain reaction amplification efficiency depended on primer sequences because the production of ASO-PCR fragments did not correlate with serum M-protein levels. However, the ASO-PCR levels in BMMNCs showed statistically significant correlations with those in PBMNCs and CD20+ CD38- B-cells. The good association between the BMMNC and PBMNC data indicated that PBMNCs could be a suitable source for monitoring minimal residual disease (MRD). In the case of cell-free DNA, ASO-PCR levels showed a unique pattern and remained high even after treatment. Because the sequence information for each ASO-PCR product was identical to the original, the cell-free DNA might also be useful for evaluating MRD. Moreover, the ASO-PCR products were clearly detected in 17 of 22 mRNA samples from CD20+ CD38- populations, suggesting that MM clones might exist in relatively earlier stages of B cells than in plasma cells. Thus, ASO-PCR analysis using various clinical materials is useful for detecting MRD in MM patients as well as for clarifying MM pathogenesis.

Aoki Y, Watanabe T, Saito Y, et al.
Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia.
Blood. 2015; 125(6):967-80 [PubMed] Article available free on PMC after 29/01/2016 Related Publications
Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

Iioka F, Akasaka T, Hayashida M, et al.
B-cell prolymphocytic leukemia carrying t(8;14)(q24;q32), associated with both autoimmune hemolytic anemia and pure red cell aplasia.
J Clin Exp Hematop. 2014; 54(3):219-24 [PubMed] Related Publications
An 80-year-old man was referred to our department because of lymphocytosis. His white cell count was 17.1 × 10(3)/μL, with 64% prolymphocytes. He did not exhibit splenomegaly or lymphadenopathy. Prolymphocytes were CD5(+), CD10(-), CD19(+), CD20(+), CD21(+weak), CD22(+), CD23(-), and HLA-DR(+), and expressed μδ/λ cell-surface immunoglobulins. G-banding and fluorescence in situ hybridization using c-MYC and immunoglobulin heavy-chain (IgH) gene probe revealed that leukemia cells carried the t(8;14)(q24;q32)/c-MYC-IgH fusion gene, and breakage and reunion occurred within the non-coding region of c-MYC exon 1 as well as the α switch region of IgH. Nine months after the initial presentation, the patient's hemoglobin level fell to 5.7 g/dL. Coombs' test was positive and marked hypoplasia of erythroid precursors was detected in his bone marrow. The patient was treated with prednisolone followed by 4 weekly doses of rituximab, which led to resolution of the anemia and complete response of the underlying leukemia. The role of t(8;14)(q24;q32)/c-MYC-IgH in the pathogenesis of B-cell prolymphocytic leukemia (B-PLL) may not be identical to that in aggressive lymphoid neoplasms, and, in the present case, autoantibodies targeting both mature red cells and erythroid precursors may have been concurrently produced in the setting of B-PLL.

Strongin DE, Groudine M, Politz JC
Nucleolar tethering mediates pairing between the IgH and Myc loci.
Nucleus. 2014 Sep-Oct; 5(5):474-81 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Gene loci on different chromosomes can preferentially colocalize in the cell nucleus. However, many of the mechanisms mediating this spatial proximity remain to be elucidated. The IgH locus on Chromosome 12 and the Myc locus on Chromosome 15 are a well-studied model for gene colocalization in murine B cells, where the two loci are positioned in close proximity at a higher than expected frequency. These gene loci are also partners in the chromosomal translocation that causes murine plasmacytoma and Burkitt's lymphoma. Because both Chromosome 12 and Chromosome 15 carry nucleolar organizer regions (NORs) in the most commonly studied mouse strains, we hypothesized that NOR-mediated tethering of the IgH and Myc loci to shared nucleoli could serve as a mechanism to drive IgH:Myc colocalization. Using mouse strains that naturally carry nucleolar organizer regions (NORs) on different sets of chromosomes, we establish that IgH and Myc are positioned proximal to nucleoli in a NOR dependent manner and show that their joint association with nucleoli significantly increases the frequency of IgH and Myc pairing. Thus we demonstrate that simple nucleolar tethering can increase the colocalization frequency of genes on NOR-bearing chromosomes.

Moharrami G, Ghorbian S, Seifi M, et al.
Detection of immunoglobulin IGH gene rearrangements on formalin-fixed, paraffin embedded tissue in lymphoid malignancies.
Cell Mol Biol (Noisy-le-grand). 2014; 60(4):43-7 [PubMed] Related Publications
Human lymphomas are aggressive malignant diseases, which can be categorized based on their B and T cell lineage. B-cell lymphomas form around 90% of the total lymphoma cases, the remnants of malignancies arise from the T cell branch. Lymphomas are mostly characterized as clonal proliferations of specific tumor cells. The detection of malignant lymphomas are extensively investigated by their morphological features, immunohistochemistry and flowcytometric immunophenotyping, but in some of cases remained unknown. The BIOMED-2 protocols were used to determine the clonality of IGH gene rearrangements in patients with lymphoma. PCR amplification was performed on FFPE of 50 patients with B-cell lymphoma, which consisted of 11 cases with HLs, 25 cases of B-NHLs and 14 cases of B-LPD (lymphoproliferative disorders) that diagnosed as unclassifiable lymphoma. The rate of positive clonality was detected in 96% (24/25) of B-NHLs, whereas in 4% (1/25) of cases clonality was showed in a polyclonal pattern. In B-HLs, 82% (9/11) of cases showed clonality and 18% (2/11) of the cases showed polyclonality. The rate of positive clonality observed in 64.3% (9/14) of cases with B-LPD and 35.7% (5/14) of cases clonality was not detected in any of immunoglobulin gene family (FR1, FR2, FR3). In groups with DLBCL, clonality was detected in 95% (19/20) of the cases. In patients diagnosed with FL and MALTs 100% cases showed clonality for complete IGH. Our study revealed that EuroClonality BIOMED-2 protocols could be considered as a valuable and reliable method for clonality detection, especially in IGH analysis.

Geller MD, Pei Y, Spurgeon SE, et al.
Chronic lymphocytic leukemia with a FGFR3 translocation: case report and literature review of an uncommon cytogenetic event.
Cancer Genet. 2014 Jul-Aug; 207(7-8):340-3 [PubMed] Related Publications
The t(4;14) (p16; q32) with fusion of the IGH (immunoglobulin heavy chain) and FGFR3 (fibroblast growth factor receptor 3) genes are rarely present in patients with chronic lymphocytic leukemia (CLL), with only two previously reported cases. We herein describe a unique case of CLL with the occurrence of a t(4;14) (p16;q32), trisomy 12, and deletion of 11q13-q23 in the same clonal cells. In contrast to myeloma, in which FGFR3 translocations are a common early cytogenetic hit, FGFR3 rearrangement in CLL appears to occur later in the disease course.

Pawlyn C, Melchor L, Murison A, et al.
Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations.
Blood. 2015; 125(5):831-40 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The acquisition of the cytogenetic abnormalities hyperdiploidy or translocations into the immunoglobulin gene loci are considered as initiating events in the pathogenesis of myeloma and were often assumed to be mutually exclusive. These lesions have clinical significance; hyperdiploidy or the presence of the t(11;14) translocation is associated with a favorable outcome, whereas t(4;14), t(14;16), and t(14;20) are unfavorable. Poor outcomes are magnified when lesions occur in association with other high-risk features, del17p and +1q. Some patients have coexistence of both good and poor prognostic lesions, and there has been no consensus on their risk status. To address this, we have investigated their clinical impact using cases in the Myeloma IX study (ISRCTN68454111) and shown that the coexistence of hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse molecular lesions, including translocations. We have also used single-cell analysis to study cases with coexistent translocations and hyperdiploidy to determine how these lesions cosegregate within the clonal substructure, and we have demonstrated that hyperdiploidy may precede IGH translocation in a proportion of patients. These findings have important clinical and biological implications, as we conclude patients with coexistence of adverse lesions and hyperdiploidy should be considered high risk and treated accordingly.

Matsuda I, Shimizu Y, Okamoto T, Hirota S
Follicular lymphoma mimicking marginal zone lymphoma in lymph node: a case report.
Int J Clin Exp Pathol. 2014; 7(10):7076-81 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Nodal follicular lymphoma (FL) is typically composed of follicular or nodular proliferation of small cleaved lymphoid cells, presumably derived from germinal center (GC) B cells. The hallmark of FL is t(14;18)(q32;q21) chromosomal translocation, which juxtaposes anti-apoptotic gene BCL2 to immunoglobulin heavy chain (IGH) promoter. Reflecting this background, FL cells are immunohistochemically positive for BCL2 as well as GC B cell markers CD10 and BCL6. It is known that low grade B-cell lymphomas, including FL, chronic lymphocytic leukemia/small lymphocytic lymphoma, and marginal zone lymphoma, are sometimes associated with marginal zone differentiation or plasmacytic differentiation. The marginal zone differentiation obscures the morphological differences among these, providing diagnostic challenges for histopathologists. In this paper, we present a case of FL, originally mimicking marginal zone lymphoma in the axillary lymph node. Subsequent bone marrow biopsy showed paratrabecular infiltration of small to medium-sized lymphoid cells. Immunohistochemical analysis of the bone marrow biopsy together with histopathology and flow cytometry of the axillary lymph node led to a final diagnosis of FL with marginal zone differentiation in the axillary lymph node and its bone marrow infiltration. Our case illustrates and reconfirms the importance of clinicopathological correlation which leads to a correct diagnosis.

Murakami I, Takata K, Matsushita M, et al.
Immunoglobulin expressions are only associated with MCPyV-positive Merkel cell carcinomas but not with MCPyV-negative ones: comparison of prognosis.
Am J Surg Pathol. 2014; 38(12):1627-35 [PubMed] Related Publications
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer, often associated with Merkel cell polyomavirus (MCPyV). Recently, immunoglobulin (Ig) expression was reported in MCC, thereby suggesting that B cells might be their cellular ancestors. We tested 30 MCCs (20 MCPyV-positive and 10 MCPyV-negative) using immunohistochemistry for the expressions of IgG, IgA, IgM, Igκ, Igλ, terminal desoxynucleotidyl transferase, paired box gene 5 (PAX5), octamer transcription factor-2 (Oct-2), and sex-determining region Y-box 11 (SOX11). We performed in situ hybridization for Igκ-mRNA or Igλ-mRNA and Ig heavy chain (IgH) gene rearrangement (IgH-R) analyses. The expressions of PAX5, TdT, Oct-2, and SOX11 were not significantly different between MCPyV-positive and MCPyV-negative MCCs. At least 1 of IgG, IgA, IgM, or Igκ was expressed in MCPyV-positive (14/20, 70%) and none in MCPyV-negative MCCs (P=0.0003). There was a higher tendency for Igκ-mRNA expression (7/19, using in situ hybridization) and IgH-R (10/20, using polymerase chain reaction) in MCPyV-positive than in MCPyV-negative MCCs (0/10 and 2/10, respectively), thus suggesting a different Ig production pattern and pathogenesis between the 2 types of MCC. Ig expression or IgH-R in MCPyV-positive MCCs might be associated with MCPyV gene integration or expression in cancer cells but do not necessarily suggest a B-cell origin for MCCs. IgH expression or IgH-R nonsignificantly correlated with improved prognosis. However, these might be important factors that influence the survival of neoplastic cells and might allow the development of novel therapies for patients with MCPyV-positive MCCs.

Xochelli A, Agathangelidis A, Kavakiotis I, et al.
Immunoglobulin heavy variable (IGHV) genes and alleles: new entities, new names and implications for research and prognostication in chronic lymphocytic leukaemia.
Immunogenetics. 2015; 67(1):61-6 [PubMed] Related Publications
Νext generation sequencing studies in Homo sapiens have identified novel immunoglobulin heavy variable (IGHV) genes and alleles necessitating changes in the international ImMunoGeneTics information system (IMGT) GENE-DB and reference directories of IMGT/V-QUEST. In chronic lymphocytic leukaemia (CLL), the somatic hypermutation (SHM) status of the clonotypic rearranged IGHV gene is strongly associated with patient outcome. Correct determination of this parameter strictly depends on the comparison of the nucleotide sequence of the clonotypic rearranged IGHV gene with that of the closest germline counterpart. Consequently, changes in the reference directories could, in principle, affect the correct interpretation of the IGHV mutational status in CLL. To this end, we analyzed 8066 productive IG heavy chain (IGH) rearrangement sequences from our consortium both before and after the latest update of the IMGT/V-QUEST reference directory. Differences were identified in 405 cases (5 % of the cohort). In 291/405 sequences (71.9 %), changes concerned only the IGHV gene or allele name, whereas a change in the percent germline identity (%GI) was noted in 114/405 (28.1 %) sequences; in 50/114 (43.8 %) sequences, changes in the %GI led to a change in the mutational set. In conclusion, recent changes in the IMGT reference directories affected the interpretation of SHM in a sizeable number of IGH rearrangement sequences from CLL patients. This indicates that both physicians and researchers should consider a re-evaluation of IG sequence data, especially for those IGH rearrangement sequences that, up to date, have a GI close to 98 %, where caution is warranted.

Swaminathan S, Müschen M
Follicular lymphoma: too many reminders for a memory B cell.
J Clin Invest. 2014; 124(12):5095-8 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Memory B cells are a dynamic subset of the mature B cell population that in some cases can reenter germinal centers (GCs) in response to iterative infections. Such a reactivation can lead to accumulation of genetic lesions in these cells, potentially from repetitive activation of the B cell mutator enzyme AID. Normal memory B cells do not survive repeated reentries into GCs. In this issue, Sungalee et al. demonstrate that memory B cells harboring the oncogenic BCL2:IGH translocation, which results in constitutive BCL2 expression, survive multiple GC entries upon repetitive immunization. Through these multiple GC reentries, the hallmark BCL2:IGH translocation enables AID-induced hypermutation and propagates clonal evolution toward malignant follicular lymphoma.

Montesinos-Rongen M, Purschke F, Küppers R, Deckert M
Immunoglobulin repertoire of primary lymphomas of the central nervous system.
J Neuropathol Exp Neurol. 2014; 73(12):1116-25 [PubMed] Related Publications
Primary lymphoma of the central nervous system (PCNSL) is a diffuse large B-cell lymphoma confined to the CNS. It has been hypothesized that antigen(s) in the CNS may trigger tumor cell proliferation. Because efforts to identify potential antigens have been unsuccessful to date, we studied the B-cell receptor in detail in a comprehensive series of 50 PCNSLs to obtain indirect information on potential antigens. Potentially functional V-D-J rearrangements were identified in all PCNSLs analyzed. Immunoglobulin heavy-chain variable gene segment (IGHV), IGHV4, was the predominant family used by 66% (33 of 50) of PCNSLs with a preferential rearrangement of the IGHV4-34 gene segment (18 [55%] of 33). The IGHV genes showed mutation frequencies from 0% to 29%, with a high average mutation frequency of 10%. In addition to 48% (24 of 50) of PCNSLs being highly mutated, 22% (11 of 50) defined a low-level mutated group. Antigen selection of the tumor cells or their precursors was indicated by replacement/silent mutation ratios and ongoing somatic hypermutation. Complementarity determining region 3 length and composition as well as the lack of stereotyped B-cell receptors suggest involvement of several antigens instead of a unique antigen recognized by the tumor cells.

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] Article available free on PMC after 01/12/2015 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] Article available free on PMC after 01/12/2015 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.

Spence JM, Abumoussa A, Spence JP, Burack WR
Intraclonal diversity in follicular lymphoma analyzed by quantitative ultradeep sequencing of noncoding regions.
J Immunol. 2014; 193(10):4888-94 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Cancers are characterized by genomic instability, and the resulting intraclonal diversity is a prerequisite for tumor evolution. Therefore, metrics of tumor heterogeneity may prove to be clinically meaningful. Intraclonal heterogeneity in follicular lymphoma (FL) is apparent from studies of somatic hypermutation (SHM) caused by activation-induced deaminase (AID) in IGH. Aberrant SHM (aSHM), defined as AID activity outside of the IG loci, predominantly targets noncoding regions causing numerous "passenger" mutations, but it has the potential to generate rare significant "driver" mutations. The quantitative relationship between SHM and aSHM has not been defined. To measure SHM and aSHM, ultradeep sequencing (>20,000-fold coverage) was performed on IGH (~1650 nt) and nine other noncoding regions potentially targeted by AID (combined 9411 nt), including the 5' untranslated region of BCL2. Single-nucleotide variants (SNVs) were found in 12/12 FL specimens (median 136 SHMs and 53 aSHMs). The aSHM SNVs were associated with AID motifs (p < 0.0001). The number of SNVs at BCL2 varied widely among specimens and correlated with the number of SNVs at eight other potential aSHM sites. In contrast, SHM at IGH was not predictive of aSHM. Tumor heterogeneity is apparent from SNVs at low variant allele frequencies; the relative number of SNVs with variable allele frequency < 5% varied with clinical grade, indicating that tumor heterogeneity based on aSHM reflects a clinically meaningful parameter. These data suggest that genome-wide aSHM may be estimated from aSHM of BCL2 but not SHM of IGH. The results demonstrate a practical approach to the quantification of intratumoral genetic heterogeneity for clinical specimens.

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.

Boyle EM, Proszek PZ, Kaiser MF, et al.
A molecular diagnostic approach able to detect the recurrent genetic prognostic factors typical of presenting myeloma.
Genes Chromosomes Cancer. 2015; 54(2):91-8 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Risk stratification in myeloma requires an accurate assessment of the presence of a range of molecular abnormalities including the differing IGH translocations and the recurrent copy number abnormalities that can impact clinical behavior. Currently, interphase fluorescence in situ hybridization is used to detect these abnormalities. High failure rates, slow turnaround, cost, and labor intensiveness make it difficult and expensive to use in routine clinical practice. Multiplex ligation-dependent probe amplification (MLPA), a molecular approach based on a multiplex polymerase chain reaction method, offers an alternative for the assessment of copy number changes present in the myeloma genome. Here, we provide evidence showing that MLPA is a powerful tool for the efficient detection of copy number abnormalities and when combined with expression assays, MLPA can detect all of the prognostically relevant molecular events which characterize presenting myeloma. This approach opens the way for a molecular diagnostic strategy that is efficient, high throughput, and cost effective.

Rodríguez-Caballero A, Henriques A, Criado I, et al.
Subjects with chronic lymphocytic leukaemia-like B-cell clones with stereotyped B-cell receptors frequently show MDS-associated phenotypes on myeloid cells.
Br J Haematol. 2015; 168(2):258-67 [PubMed] Related Publications
An increasing body of evidence suggests the potential occurrence of antigen encounter by the cell of origin in chronic lymphocytic leukaemia (CLL) and CLL-like monoclonal B-cell lymphocytosis (MBL). However, the scenario in which this event might occur remains unknown. In order to gain insight into this scenario we investigated the molecular, cytogenetic and haematological features of 223 CLL-like (n = 84) and CLL (n = 139) clones with stereotyped (n = 32) versus non-stereotyped (n = 191) immunoglobulin heavy chain variable region (IGHV) amino acid sequences. Overall, stereotyped CLL-like MBL and CLL clones showed a unique IGHV profile, associated with higher IGHV1 and lower IGHV3 gene family usage (P = 0·03), longer IGHV complementary determining region 3 (HCDR3) sequences (P = 0·007) and unmutated IGHV (P < 0·001) versus non-stereotyped clones. Whilst the overall size of the stereotyped B-cell clones in peripheral blood did not appear to be associated with the CLL-related cytogenetic profile of B-cells (P > 0·05), it did show a significant association with the presence of myelodysplastic syndrome (MDS)-associated immunophenotypes on peripheral blood neutrophils and/or monocytes (P = 0·01). Altogether our results point to the potential involvement of different selection forces in the expansion of stereotyped vs. non-stereotyped CLL and CLL-like MBL clones, the former being potentially favoured by an underlying altered haematopoiesis.

Horn H, Staiger AM, Vöhringer M, et al.
Diffuse large B-cell lymphomas of immunoblastic type are a major reservoir for MYC-IGH translocations.
Am J Surg Pathol. 2015; 39(1):61-6 [PubMed] Related Publications
The immunoblastic variant of diffuse large B-cell lymphoma (IB-DLBCL) has recently been recognized as an aggressive lymphoma type with inferior prognosis as compared with other DLBCL variants. At the same time, the presence of MYC rearrangements in DLBCL has been shown to indicate shorter survival in R-CHOP-treated patients. In this study, we investigated the occurrence of MYC gene rearrangements in IB-DLBCL versus non-IB-DLBCL in a large series. Using fluorescence in situ hybridization with an MYC break-apart and MYC-IGH fusion probe, we found that 13/39 evaluable IB-DLBCLs (33%) harbor translocations involving MYC, in contrast with only 5/68 (7%) in the non-IB-DLBCL group (P<0.01). The immunoglobulin heavy chain gene (IGH) was the translocation partner in all rearrangements (100%) involving MYC in IB-DLBCL, which is in contrast to what has been reported for DLBCL in the literature (50% to 70%). Moreover, MYC rearrangements occurred as the sole translocation in the majority of cases (77%), whereas across all DLBCLs the majority of MYC-rearranged cases carry additional rearrangements of either BCL2 and/or BCL6 genes (between 58% and 83% of cases). Finally, MYC-rearranged IB-DLBCLs were CD10 positive in 62% (8/13), whereas this was an uncommon feature in MYC germline IB-DLBCLs (15%). In conclusion, IB-DLBCLs are genetically characterized by frequent MYC-IGH translocations that often occur without additional BCL2 and/or BCL6 translocations. The activation of MYC, therefore, may be an important pathogenetic feature in IB-DLBCL.

Petrikkos L, Kyrtsonis MC, Roumelioti M, et al.
Clonotypic analysis of immunoglobulin heavy chain sequences in patients with Waldenström's macroglobulinemia: correlation with MYD88 L265P somatic mutation status, clinical features, and outcome.
Biomed Res Int. 2014; 2014:809103 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
We performed IGH clonotypic sequence analysis in WM in order to determine whether a preferential IGH gene rearrangement was observed and to assess IGHV mutational status in blood and/or bone marrow samples from 36 WM patients. In addition we investigated the presence of MYD88 L265P somatic mutation. After IGH VDJ locus amplification, monoclonal VDJ rearranged fragments were sequenced and analyzed. MYD88 L265P mutation was detected by AS-PCR. The most frequent family usage was IGHV3 (74%); IGHV3-23 and IGHV3-74 segments were used in 26% and 17%, respectively. Somatic hypermutation was seen in 91% of cases. MYD88 L265P mutation was found in 65,5% of patients and absent in the 3 unmutated. These findings did not correlate with clinical findings and outcome. Conclusion. IGH genes' repertoire differed in WM from those observed in other B-cell disorders with a recurrent IGHV3-23 and IGHV3-74 usage; monoclonal IGHV was mutated in most cases, and a high but not omnipresent prevalence of MYD88 L265P mutation was observed. In addition, the identification of 3 patients with unmutated IGHV gene segments, negative for the MYD88 L265P mutation, could support the hypothesis that an extra-germinal B-cell may represent the originating malignant cell in this minority of WM patients.

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