Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

NSD2 (nuclear receptor binding SET domain protein 2 )

Written2012-05Eva Martinez-Garcia, Jonathan D Licht
Feinberg School of Medicine, Northwestern University, Hematology/Oncology Division, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA
This article is an update of :
2008-11Eva Martinez-Garcia, Jonathan D Licht
Feinberg School of Medicine, Northwestern University, Hematology/Oncology Division, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA

(Note : for Links provided by Atlas : click)


HGNC (Hugo) NSD2
HGNC Alias symbMMSET
HGNC Alias namemultiple myeloma SET domain containing protein
HGNC Previous nameWHSC1
HGNC Previous nameWolf-Hirschhorn syndrome candidate 1
LocusID (NCBI) 7468
Atlas_Id 42809
Location 4p16.3  [Link to chromosome band 4p16]
Location_base_pair Starts at 1892782 and ends at 1982207 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping NSD2.png]
Local_order From the telomeric to centromeric end (Chesi et al., 1998).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
DNAH12 (3p14.3)::NSD2 (4p16.3)FGFR3 (4p16.3)::NSD2 (4p16.3)GSTP1 (11q13.2)::NSD2 (4p16.3)
NAP1L1 (12q21.2)::NSD2 (4p16.3)NASP (1p34.1)::NSD2 (4p16.3)NSD2 (4p16.3)::CHN2 (7p14.3)
NSD2 (4p16.3)::FAM53A (4p16.3)NSD2 (4p16.3)::FOXP1 (3p13)NSD2 (4p16.3)::GPR34 (Xp11.4)
NSD2 (4p16.3)::GRK4 (4p16.3)NSD2 (4p16.3)::GSDMB (17q12)NSD2 (4p16.3)::GSDMB (17q21.1)
NSD2 (4p16.3)::ID4 (6p22.3)NSD2 (4p16.3)::IGF2BP1 (17q21.32)NSD2 (4p16.3)::IL3 (5q31.1)
NSD2 (4p16.3)::IMMP2L (7q31.1)NSD2 (4p16.3)::IRF4 (6p25.3)NSD2 (4p16.3)::IRF8 (16q24.1)
NSD2 (4p16.3)::KDM4C (9p24.1)NSD2 (4p16.3)::KDSR (18q21.33)NSD2 (4p16.3)::LHX2 (9q33.3)
NSD2 (4p16.3)::LHX4 (1q25.2)NSD2 (4p16.3)::MAF (16q23.2)NSD2 (4p16.3)::MAFB (20q12)
NSD2 (4p16.3)::MALT1 (18q21.32)NSD2 (4p16.3)::NSD2 (4p16.3)NSD2 (4p16.3)::PIBF1 (13q21.33)
NSD2 (4p16.3)::PIBF1 (13q22.1)NSD2 (4p16.3)::PRKCZ (1p36.33)NSD2 (4p16.3)::REC114 (15q24.1)
NSD2 (4p16.3)::TACC3 (4p16.3)NSD2 (4p16.3)::WWOX (16q23.1)NSD2 (4p16.3)::ZEB2 (2q22.3)
ORAI2 (7q22.1)::NSD2 (4p16.3)RCN2 (15q24.3)::NSD2 (4p16.3)REST (4q12)::NSD2 (4p16.3)
SPATA48 (7p12.2)::NSD2 (4p16.3)ST6GAL1 (3q27.3)::NSD2 (4p16.3)STPG1 (1p36.11)::NSD2 (4p16.3)
TRG (7p14)::NSD2 (4p16.3)WIPI1 (17q24.2)::NSD2 (4p16.3)


Description Spans 120 Kb of genomic DNA and consists of 24 exons transcribed into a mRNA that undergoes alternative splicing (Marango et al., 2007).
Transcription Undergoes complex alternative splicing. Most primary trancripts splice directly to exon 3, which contains the proper translation initiation site, though small fraction of transcripts retain upstream sequence including exons 1 and 2 (Keats et al., 2005).


  Conserved domains present in MMSET variants (adapted from Keats et al., 2005).
Description Alternative splicing of exon 4 to 4a instead of 5 generates de MMSET III protein (273 amino acids, 32 kDa), due to the presence of an in-frame stop codon in exon 4a. Alternative splicing of exon 10 to 11 or 12 generates MMSET I (647 amino acids, 75 kDa) or the full-length MMSET II (1365 amino acids, 155 kDa) respectively, due to the presence of an in-frame stop codon in exon 11. A third transcript initiated within a middle intron of MMSET, encoding a mRNA comprising the 3'half of MMSET gene was identified and encodes a protein named RE-IIBP.
The long transcript, MMSET II, contains: 2 PWWP (proline-tryptophan-tryptophan-proline) domain, a HMG box (high mobility group), 4 PHD (plant-home domain)- type zinc finger motifs and a SET domain. MMSET I contains only a PWWP and a HMG domain and REIIBP, 2 PHD, a PWWP and a SET domain (Keats et al., 2005).
Expression Widely expressed.
It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients (Stec et al., 1998). Recently it has been shown that MMSET is highly expressed in different tumor types such as carcinomas of the gastrointestinal tract (stomach, colon, anal canal), small cell lung carcinoma, bladder, female genitals and skin (Hudlebusch et al., 2011). It is also highly expressed and associated with aggressive neuroblastoma (Hudlebusch et al., 2011).
Localisation Homogenous pattern within the nucleus, excluded from the nucleolus.
Function Histone methyltransferase that leads to dimethylation of histone 3 lysine 36 (H3K36) (Marango et al., 2008; Martinez-Garcia et al., 2011; Kuo et al., 2011). WHSC1 is involved in the cellular response to DNA damage through its activity on H4K20 residue (Hajdu et al., 2011; Pei et al., 2011).

Implicated in

Entity Multiple myeloma
Note WHSC1 was identified as a gene involved in the translocation present in approximately 15% to 20% of MM (Chesi et al., 1998). This subtype of myeloma with t(4;14)(p16;q32) has a poor prognosis with frequent relapse after autologous stem-cell transplantation (Moreau et al., 2002; Chang et al., 2004).
The t(4;14) Translocation Identifies MMSET as an oncogene in Multiple Myeloma. The gene rearrangement links the Eµ enhancer 5' to MMSET, driving transcription of MMSET from the telomeric-centromeric direction. The reciprocal translocation links an Ig enhancer 3' to the FGFR3 locus stimulating transcription in the centromeric-telomeric direction.
Entity Glioblastoma
Note WHSC1 expression level is correlated with glioma grade, and it appears to be directly involved in the proliferative capacity of GBM cells in vitro (Li et al., 2008).
Entity Neuroblastoma
Note MMSET is highly expressed in 75% neuroblastomas and is associated with aggressiveness. MMSET is associated with poor prognostic markers, poor survival, and progression; and is required for proliferation of neuroblastoma cells (Hudlebusch et al., 2011).
Entity Urinary bladder cancer
Note In urinary bladder cancer, MMSET protein was detected in 40% of the cases and was associated with aggressiveness: expression levels correlated with poor prognostic markers (stage, grade, age, and type of tumor growth), and progression (Hudlebusch et al., 2011).
Entity Prostate cancer
Note Analysis of microarray databases indicates that MMSET expression rises in the progression from benign prostatic epithelium to localized and metastatic PCa. Overexpression of MMSET in RWPE-1 cells is accompanied by an epithelial to mesenchymal transition (EMT), characterized by a change in cell morphology and increased expression of mesenchymal markers vimentin and N-cadherin. Twist1, an EMT promoting gene, was strongly regulated by MMSET (Ezponda-Itoiz et al., 2012).
Entity Wolf-Hirschhorn syndrome (WHS)
Note Wolf-Hirshhorn syndrome is caused by a partial deletion of chromosome 4p, particularly in the region of WHSC1 and WHSC2. About 87% of cases represent a de novo deletion, while about 13% are inherited from a parent with a chromosome translocation.


The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant.
Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI, Reece D, Chun K, Keith Stewart A.
Br J Haematol. 2004 Apr;125(1):64-8.
PMID 15015970
The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts.
Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL.
Blood. 1998 Nov 1;92(9):3025-34.
PMID 9787135
The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer.
Ezponda T, Popovic R, Shah MY, Martinez-Garcia E, Zheng Y, Min DJ, Will C, Neri A, Kelleher NL, Yu J, Licht JD.
Oncogene. 2012 Jul 16. doi: 10.1038/onc.2012.297. [Epub ahead of print]
PMID 22797064
Wolf-Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage.
Hajdu I, Ciccia A, Lewis SM, Elledge SJ.
Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13130-4. Epub 2011 Jul 25.
PMID 21788515
MMSET is highly expressed and associated with aggressiveness in neuroblastoma.
Hudlebusch HR, Skotte J, Santoni-Rugiu E, Zimling ZG, Lees MJ, Simon R, Sauter G, Rota R, De Ioris MA, Quarto M, Johansen JV, Jorgensen M, Rechnitzer C, Maroun LL, Schroder H, Petersen BL, Helin K.
Cancer Res. 2011 Jun 15;71(12):4226-35. Epub 2011 Apr 28.
PMID 21527557
Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients.
Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M, Bergsagel PL, Larratt LM, Mant MJ, Reiman T, Belch AR, Pilarski LM.
Blood. 2005 May 15;105(10):4060-9. Epub 2005 Jan 27.
PMID 15677557
NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming.
Kuo AJ, Cheung P, Chen K, Zee BM, Kioi M, Lauring J, Xi Y, Park BH, Shi X, Garcia BA, Li W, Gozani O.
Mol Cell. 2011 Nov 18;44(4):609-20.
PMID 22099308
Identification of a novel proliferation-related protein, WHSC1 4a, in human gliomas.
Li J, Yin C, Okamoto H, Mushlin H, Balgley BM, Lee CS, Yuan K, Ikejiri B, Glasker S, Vortmeyer AO, Oldfield EH, Weil RJ, Zhuang Z.
Neuro Oncol. 2008 Feb;10(1):45-51. Epub 2008 Jan 8.
PMID 18182627
The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor.
Marango J, Shimoyama M, Nishio H, Meyer JA, Min DJ, Sirulnik A, Martinez-Martinez Y, Chesi M, Bergsagel PL, Zhou MM, Waxman S, Leibovitch BA, Walsh MJ, Licht JD.
Blood. 2008 Mar 15;111(6):3145-54. Epub 2007 Dec 21.
PMID 18156491
The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells.
Martinez-Garcia E, Popovic R, Min DJ, Sweet SM, Thomas PM, Zamdborg L, Heffner A, Will C, Lamy L, Staudt LM, Levens DL, Kelleher NL, Licht JD.
Blood. 2011 Jan 6;117(1):211-20. Epub 2010 Oct 25.
PMID 20974671
Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy.
Moreau P, Facon T, Leleu X, Morineau N, Huyghe P, Harousseau JL, Bataille R, Avet-Loiseau H; Intergroupe Francophone du Myelome.
Blood. 2002 Sep 1;100(5):1579-83.
PMID 12176874
MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites.
Pei H, Zhang L, Luo K, Qin Y, Chesi M, Fei F, Bergsagel PL, Wang L, You Z, Lou Z.
Nature. 2011 Feb 3;470(7332):124-8.
PMID 21293379
WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.
Stec I, Wright TJ, van Ommen GJ, de Boer PA, van Haeringen A, Moorman AF, Altherr MR, den Dunnen JT.
Hum Mol Genet. 1998 Jul;7(7):1071-82.
PMID 9618163


This paper should be referenced as such :
Martinez-Garcia, E ; Licht, JD
WHSC1 (Wolf-Hirschhorn syndrome candidate 1)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(10):743-745.
Free journal version : [ pdf ]   [ DOI ]
History of this paper:
Martinez-Garcia, E ; Licht, JD. WHSC1 (Wolf-Hirschhorn syndrome candidate 1). Atlas Genet Cytogenet Oncol Haematol. 2009;13(10):739-741.

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 3 ]
  Multiple myeloma (published in 2004)
Multiple Myeloma
t(4;14)(p16;q32) IGH::FGFR3 and WHSC1

External links

HGNC (Hugo)NSD2   12766
Atlas Explorer : (Salamanque)NSD2
Entrez_Gene (NCBI)NSD2    nuclear receptor binding SET domain protein 2
GeneCards (Weizmann)NSD2
Ensembl hg19 (Hinxton)ENSG00000109685 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000109685 [Gene_View]  ENSG00000109685 [Sequence]  chr4:1892782-1982207 [Contig_View]  NSD2 [Vega]
ICGC DataPortalENSG00000109685
TCGA cBioPortalNSD2
AceView (NCBI)NSD2
Genatlas (Paris)NSD2
SOURCE (Princeton)NSD2
Genetics Home Reference (NIH)NSD2
Genomic and cartography
GoldenPath hg38 (UCSC)NSD2  -     chr4:1892782-1982207 +  4p16.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NSD2  -     4p16.3   [Description]    (hg19-Feb_2009)
GoldenPathNSD2 - 4p16.3 [CytoView hg19]  NSD2 - 4p16.3 [CytoView hg38]
Genome Data Viewer NCBINSD2 [Mapview hg19]  
OMIM194190   602952   619695   
Gene and transcription
Genbank (Entrez)AB029013 AF071593 AF071594 AF083386 AF083387
RefSeq transcript (Entrez)NM_001042424 NM_007331 NM_014919 NM_133330 NM_133331 NM_133332 NM_133333 NM_133334 NM_133335 NM_133336
Consensus coding sequences : CCDS (NCBI)NSD2
Gene ExpressionNSD2 [ NCBI-GEO ]   NSD2 [ EBI - ARRAY_EXPRESS ]   NSD2 [ SEEK ]   NSD2 [ MEM ]
Gene Expression Viewer (FireBrowse)NSD2 [ Firebrowse - Broad ]
GenevisibleExpression of NSD2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7468
GTEX Portal (Tissue expression)NSD2
Human Protein AtlasENSG00000109685-NSD2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)NSD2
Human Protein Atlas [tissue]ENSG00000109685-NSD2 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed152 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Jan 20 14:20:13 CET 2022

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us