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t(14;19)(q32;q13) IGH/Various Partners

Written2019-09Jean Loup Huret
jean-loup.huret@atlasgeneticsoncology.org

Abstract Review on the various t(14;19)(q32;q13), with data on clinics, and the genes involved.

Keywords Chromosome 14; chromosome 19; IGH; BCL3; CEBPA; CEBPG; ERF; FOSB; NECTIN2; PPP1R15A; SPIB; chronic lymphocytic leukemia; nodal marginal zone B-cell lymphoma; mature B-cell neoplasm; diffuse large B-cell lymphoma; splenic marginal zone B-cell lymphoma; follicular lymphoma; bilineage leukemia; Burkitt lymphoma; chronic myeloid leukemia; lymphoplasmacytic lymphoma; mantle cell lymphoma; Hodgkin disease, multiple myeloma.

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Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9823/3 Chronic lymphocytic leukaemia /small lymphocytic lymphoma
ICD-Morpho 9699/3 Extranodal marginal zone lymphoma of mucosa- associated lymphoid tissue (MALT lymphoma); Nodal marginal zone lymphoma; Paediatric nodal marginal zone lymphoma
ICD-Morpho 9680/3 Diffuse large B-cell lymphoma (DLBCL), NOS; Primary DLBCL of the CNS; Primary cutaneous DLBCL, leg type; EBV positive DLBCL of the elderly; DLBCL associated with chronic inflammation; B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
ICD-Morpho 9690/3 Follicular lymphoma; Paediatric follicular lymphoma
ICD-Morpho 9808/3 Mixed phenotype acute leukaemia, B/myeloid, NOS 152
ICD-Morpho 9687/3 Burkitt lymphoma
ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
ICD-Morpho 9671/3 Lymphoplasmacytic lymphoma
ICD-Morpho 9673/3 Mantle cell lymphoma
ICD-Morpho 9650/3 Classical Hodgkin lymphoma
ICD-Morpho 9732/3 Plasma cell myeloma / Multiple myeloma
Atlas_Id 1462

Clinics and Pathology

Disease According to a search in Mitelman database "Cases Quick Searcher", 181 cases of t(14;19)(q32;q13) are available in the literature: 104 chronic lymphocytic leukemia cases (CLL), 30 acute B-cell lymphoblastic leukemia, 13 nodal marginal zone B-cell lymphoma, 12 mature B-cell neoplasm not otherwise specified (NOS), 10 diffuse large B-cell lymphoma, 5 splenic marginal zone B-cell lymphoma, 2 follicular lymphoma, 1 bilineage leukemia, 1 Burkitt lymphoma, 1 chronic myeloid leukemia, 1 lymphoplasmacytic lymphoma, and 1 mantle cell lymphoma.
A t(14;19)(q32;q13) IGH/BCL3 has been found in chronic lymphocytic leukemia, mature B-cell neoplasm NOS, diffuse large B-cell lymphoma, bilineage leukemia, follicular lymphoma, Hodgkin disease, nodal marginal zone B-cell lymphoma, and splenic marginal zone B-cell lymphoma.
A t(14;19)(q32;q13) IGH/CEBPA or CEBPG, but also other translocations with IGH fused to CCAAT/enhancer binding proteins (CEBPB (20q13), CEBPD (8p11), CEBPE (14q11)) has been found so far only in acute B-cell lymphoblastic leukemia.
Other t(14;19)(q32;q13) with IGH involvement have been found in multiple myeloma (IGH/ERF, IGH/FOSB, IGH/PPP1R15A (Cleynen et al., 2017)) and diffuse large B-cell lymphoma (IGH/NECTIN2, IGH/SPIB (Lenz et al 2007; Otto et al., 2016)).
Cytogenetics t(14;19)(q32;q13) IGH/BCL3
t(14;19)(q32;q13) IGH/CEBPA or CEBPG
t(14;19)(q32;q13)IGH/ERF
t(14;19)(q32;q13) IGH/FOSB
t(14;19)(q32;q13) IGH/NECTIN2
t(14;19)(q32;q13) IGH/PPP1R15A
t(14;19)(q32;q13) IGH/SPIB

Cytogenetics

 
  IGH partners in the t(14;19)(q32;q13)
GeneChrom. BandStarts-Ends (from pter)
CEBPA19q13.1133,299,934 - 33,302,564
CEBPG19q13.1133,373,669 - 33,382,686
ERF19q13.242,247,561 - 42,255,164
BCL319q13.3244,748,721 - 44,760,044
NECTIN219q13.3244,846,136 - 44,878,941
FOSB19q13.3245,467,995 - 45,475,179
PPP1R15A19q13.3348,872,392 - 48,876,062
SPIB19q13.3350,418,938 - 50,431,052

Genes involved and Proteins

Gene NameIGH (immunoglobulin heavy locus)
Location 14q32.33
Gene NameBCL3
Location 19q13.32
Note Starts at 44748721 and ends at 44760044 bp from pter.
Protein 454 amino acids. BCL3 contains seven ankyrin repeats (aa 134-163, 171-200, 204-235, 241-270, 275-304, 308-337, 338-367). BCL3 is a member of the I-kappaB family ( NFKBIA (NFKB inhibitor alpha), NFKBIB (NFKB inhibitor beta) and others), whose proteins regulate the NF-kB family of transcription factors. BCL3 interacts with NFKB1 and NFKB2 (NF-kappaB p50 and p52). NF-kB plays a major role in B-cell development. BCL3 is induced by LIF and plays a role in the maintenance of pluripotency. BCL3 stimulates cell-cycle progression in a breast cancer cell line. BCL3 interacts with TRAF6. The ankyrin repeats of BCL3 bind the RING domain of TRAF6. TRAF6 mediate a NF-kB signaling via BCL3 to promote osteoclastogenesis (Otsuka et al., 2018; Wang et al., 2018)
Gene NameCEBPA (CCAAT/enhancer binding protein (C/EBP), alpha)
Location 19q13.11
Note Starts at 33299934 and ends at 33302564 bp from pter.
Protein 358 amino acids. CEBPA contains a bzip (aa 282-345, with a basic motif (aa 286-313) and a leucine zipper (aa 317-345)). Transcription factor. Binds the consensus DNA sequence T[TG]NNGNAA[TG] as a homo or heterodimer. Key factor driving myeloid cell differentiation of hematopoietic stem cells and also driving differentiation of other cell lineages (Tian and Graf, 2014).
Gene NameCEBPG (CCAAT enhancer binding protein gamma)
Location 19q13.11
Note Starts at 33373669 and ends at 33382686 bp from pter. CEBPG is located only 71 kb distal of CEBPA.
Protein 150 amino acids. CEBPAG contains a bzip (aa 62-125, with a basic motif (aa 66-93) and a leucine zipper (aa 97-118)). Transcription factor. CEBPB homodimers are cytostatic and promote cell cycle arrest and senescence. Conversely, CEBPB/CEBPG heterodimers display reduced transcriptional potential. However, CEBPG deletion did not alter hematopoietic stem and progenitor cell ability to commit to the myeloid lineage. ATF4/CEBPG heterodimer is an antioxidant regulator that controls redox homeostasis in normal and cancerous cells. CEBPG acts as a negative regulator of senescence and promotes proliferation of multiple cell types (Huggins et al., 2013; Huggins et al., 2015; Kardosova et al., 2018).
Gene NameERF (ETS2 repressor factor)
Location 19q13.2
Note Starts at 42247561 and ends at 42255164 bp from pter.
Protein 548 amino acids. ERF contains an ETS domain (aa 29-106), an ERK interaction domain (aa 294-385), and a repressor domain (aa 472-530). Member of the ETS family of transcription factors. ERF translocates to the nucleus, where it binds to enhancers of RAS targets, pluripotency and mitogenic factors. ERF may play a role in limiting mouse embryonic stem cells differentiation. Loss-of-function ERF germline mutations are implicated in an autosomal form of craniosynostosis (Mayor-Ruiz et al., 2018).
Gene NameFOSB (FosB proto-oncogene, AP-1 transcription factor subunit)
Location 19q13.32
Note Starts at 45467995 and ends at 45475179 bp from pter.
FOSB is also called AP-1 (which is confusing with the "AP-1 complex").
Protein 338 amino acids. FOSB contains a bzip (aa 155-218, with a basic motif (aa 157-182) and a leucine zipper (aa 183-211)). Transcription factor, member of the AP-1 Transcription Factors family: AP-1 complex is a dimeric complex composed of members from the JUN, FOS ( FOS, FOSB, FOSL1 and FOSL2 (FRA-1 and FRA-2)), ATF, or MAF protein families. The sequence elements to which AP-1 transcription factors bind differ depending on the distinctive homo- or hetero-dimer combinations. FOS proteins bind the TRE sequence: TGACTCA. FOS proteins only form hetero-dimers (review in Garces de Los Fayos Alonso et al., 2018).
ΔFosB, a splice variant of FOSB is induced by stress, antidepressants, and drugs abuse in brain regions such as the prefrontal cortex and the hippocampus (Palafox-Sanchez et al., 2019).
Gene NameNECTIN2 (nectin cell adhesion molecule 2)
Location 19q13.32
Note Starts at 44846136 and ends at 44878941 bp from pter.
NECTIN2 is also called PVRL2 (poliovirus receptor-related 2).
Protein NECTIN2 is a cell membrane protein involved in immune checkpoint, part of the TIGIT-PVR/PVRL2 axis. NECTIN2 is composed of a signal peptide (amino acids (aa) 1-31), an extracellular domain (aa 32-360), a transmembrane domain (aa 361-381), and a cytoplasmic domain (aa 382-538). NECTIN2 also interacts with PVRIG CD226, CD96 to stimulate or inhibit lymphocyte cell signaling (Stamm et al., 2018; Whelan et al., 2019).
Gene NamePPP1R15A (protein phosphatase 1 regulatory subunit 15A)
Location 19q13.33
Note Starts at 48872392 and ends at 48876062 bp from pter
PPP1R15A is also called GADD34.
Protein 674 amino acids. PPP1R15A inhibits the proteasomal degradation of MCL1 and enhances MCL1 protein stability. PPP1R15A overexpression promotes MAPK signaling pathway through TRAF6 and TAB1, which mediates the up-regulation of MCL1 (Song et al., 2019).
Gene NameSPIB (Spi-B transcription factor)
Location 19q13.33
Note Starts at 50418938 and ends at 50431052 bp from pter.
Protein 262 amino acids. SPIB contains two transactivation domains (aa 1-31 and 41-61). Binds to the nucleotide sequence GGAA. Transcriptional activator of B-cell development and differentiation. SPI1 (spleen focus forming virus (SFFV) proviral integration oncogene spi1, also known as PU.1) and SPIB control many components of the B-cell receptor (BCR) pathway. SPI1 and SPIB are partially redundant. Inactivation of SPI1 and SPIB in B-cell progenitors blocks the development at the pre-B-cell stage and induces pre-B acute lymphoblastic leukemia. Inactivation SPI1 and SPIB in mature B cells prevents germinal centers development. SPI1 and SPIB negatively regulate plasma cell differentiation (Willis et al., 2017).

Result of the chromosomal anomaly

Hybrid gene
Description CEBPA and CEBPG cases: The breakpoints clustered within the 3' UTR of CEBPA in most cases, and was 31 kb centromeric of CEBPA in one case. The breakpoint was 52 kb centromeric of CEBPG (Akasaka et al., 2007). NECTIN2 case: The breakpoint in NECTIN2 was located in exon 1 in the 5'untranslated region at position 45,349,458 from the p terminus of chromosome 19 (Otto et al., 2016).
  
Fusion Protein
Oncogenesis In the case reported by Otto et al., 2016, NECTIN2 was expressed at a significantly higher level than in the other 363 DLBCL studied.
  

To be noted

Additional cases of t(14;19)(q32;q13)IGH/ERF, t(14;19)(q32;q13) IGH/FOSB, t(14;19)(q32;q13) IGH/NECTIN2, t(14;19)(q32;q13) IGH/PPP1R15A and t(14;19)(q32;q13) IGH/SPIB are needed to delineate the epidemiology of these rare entities:
you are welcome to submit a paper to our new Case Report section.

Bibliography

CEBPA (CCAAT/enhancer binding protein (C/EBP), alpha)
Tian TV, Graf TS
Atlas Genet Cytogenet Oncol Haematol. 2015;19(4):249-255.
 
Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R, Karran EL, Brown DG, Cain K, Harder L, Gesk S, Martin-Subero JI, Atherton MG, Brüggemann M, Calasanz MJ, Davies T, Haas OA, Hagemeijer A, Kempski H, Lessard M, Lillington DM, Moore S, Nguyen-Khac F, Radford-Weiss I, Schoch C, Struski S, Talley P, Welham MJ, Worley H, Strefford JC, Harrison CJ, Siebert R, Dyer MJ
Blood 2007 Apr 15;109(8):3451-61
PMID 17170124
 
Expressed fusion gene landscape and its impact in multiple myeloma
Cleynen A, Szalat R, Kemal Samur M, Robiou du Pont S, Buisson L, Boyle E, Chretien ML, Anderson K, Minvielle S, Moreau P, Attal M, Parmigiani G, Corre J, Munshi N, Avet-Loiseau H
Nat Commun 2017 Dec 1;8(1):1893
PMID 29196615
 
The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas
Garces de Los Fayos Alonso I, Liang HC, Turner SD, Lagger S, Merkel O, Kenner L
Cancers (Basel) 2018 Mar 28;10(4)
PMID 29597249
 
C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4
Huggins CJ, Mayekar MK, Martin N, Saylor KL, Gonit M, Jailwala P, Kasoji M, Haines DC, Quiñones OA, Johnson PF
Mol Cell Biol 2015 Dec 14;36(5):693-713
PMID 26667036
 
C/EBPγ is dispensable for steady-state and emergency granulopoiesis
Kardosova M, Zjablovskaja P, Danek P, Angelisova P, de Figueiredo-Pontes LL, Welner RS, Brdicka T, Lee S, Tenen DG, Alberich-Jorda M
Haematologica 2018 Aug;103(8):e331-e335
PMID 29567783
 
Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma
Lenz G, Nagel I, Siebert R, Roschke AV, Sanger W, Wright GW, Dave SS, Tan B, Zhao H, Rosenwald A, Muller-Hermelink HK, Gascoyne RD, Campo E, Jaffe ES, Smeland EB, Fisher RI, Kuehl WM, Chan WC, Staudt LM
J Exp Med 2007 Mar 19;204(3):633-43
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ERF deletion rescues RAS deficiency in mouse embryonic stem cells
Mayor-Ruiz C, Olbrich T, Drosten M, Lecona E, Vega-Sendino M, Ortega S, Dominguez O, Barbacid M, Ruiz S, Fernandez-Capetillo O
Genes Dev 2018 Apr 1;32(7-8):568-576
PMID 29650524
 
Identification of KLF9 and BCL3 as transcription factors that enhance reprogramming of primordial germ cells
Otsuka K, Takehara A, Chiba N, Matsui Y
PLoS One 2018 Oct 4;13(10):e0205004
PMID 30286177
 
Novel IGH and MYC Translocation Partners in Diffuse Large B-Cell Lymphomas
Otto C, Scholtysik R, Schmitz R, Kreuz M, Becher C, Hummel M, Rosenwald A, Trümper L, Klapper W, Siebert R, Küppers R; 'Molecular Mechanisms in Malignant Lymphomas Network Project
Genes Chromosomes Cancer 2016 Dec;55(12):932-943
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Differential Expression of Striatal FosB mRNA and FosB mRNA After Different Levodopa Treatment Regimens in a Rat Model of Parkinson's Disease
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Neurotox Res 2019 Apr;35(3):563-574
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The regulatory protein GADD34 inhibits TRAIL-induced apoptosis via TRAF6/ERK-dependent stabilization of myeloid cell leukemia 1 in liver cancer cells
Song P, Yang S, Hua H, Zhang H, Kong Q, Wang J, Luo T, Jiang Y
J Biol Chem 2019 Apr 12;294(15):5945-5955
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Interaction of PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune checkpoint axis and therapeutic target in cancer
Stamm H, Wellbrock J, Fiedler W
Mamm Genome 2018 Dec;29(11-12):694-702
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BCL3 regulates RANKL-induced osteoclastogenesis by interacting with TRAF6 in bone marrow-derived macrophages
Wang K, Li S, Gao Y, Feng X, Liu W, Luo R, Song Y, Ji Tu, Liu Y, Yang C
Bone 2018 Sep;114:257-267
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PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8(+) T-cell Function
Whelan S, Ophir E, Kotturi MF, Levy O, Ganguly S, Leung L, Vaknin I, Kumar S, Dassa L, Hansen K, Bernados D, Murter B, Soni A, Taube JM, Fader AN, Wang TL, Shih IM, White M, Pardoll DM, Liang SC
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Environmental sensing by mature B cells is controlled by the transcription factors PU
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Citation

This paper should be referenced as such :
Huret JL
t(14;19)(q32;q13) IGH/Various Partners;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t1419q32q13IGH_VarPartnersID1462.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(14;19)(q32;q13) IGH/BCL3
 t(14;19)(q32;q13) IGH/CEBPA
 t(14;19)(q32;q13) IGH/CEBPG
 t(14;19)(q32;q13)IGH/ERF
 t(14;19)(q32;q13) IGH/FOSB
 t(14;19)(q32;q13) IGH/NECTIN2
 t(14;19)(q32;q13) IGH/PPP1R15A
 t(14;19)(q32;q13) IGH/SPIB


External links

Mitelman databaset(14;19)(q32;q13)
Mitelman databaset(14;19)(q32;q13)
Mitelman databaset(14;19)(q32;q13)
Mitelman databaset(14;19)(q32;q13)IGH/ERF
Mitelman databaset(14;19)(q32;q13)
Mitelman databaset(14;19)(q32;q13)
Mitelman databaset(14;19)(q32;q13)
Mitelman databaset(14;19)(q32;q13)
arrayMap (UZH-SIB Zurich)Morph ( 9823/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9699/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9680/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9690/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9808/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9687/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9975/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9671/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9673/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9650/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9732/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
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