| Entity | Multiple myeloma (MM) |
| Note | WHSC1 was identified as a gene involved in the t(4;14)(p16;q32) 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). |
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| 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. |
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| 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). |
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| 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). |
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| 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). |
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| 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). |
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| 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. |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. |
| Hudlebusch HR, Santoni-Rugiu E, Simon R, Ralfkiaer E, Rossing HH, Johansen JV, Jorgensen M, Sauter G, Helin K. |
| Clin Cancer Res. 2011 May 1;17(9):2919-33. Epub 2011 Mar 8. |
| PMID 21385930 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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