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Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies

Leukemia volume 28, pages 198–201 (2014)Cite this article

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Acute lymphoblastic leukemia (ALL) is a neoplasm of lymphocytic progenitors and represents the most common malignancy in children. The disease is frequently characterized by large-scale chromosomal alterations including hyper- or hypodiploidy, translocations, deletions and insertions. Genomic profiling of ALL patient samples identified frequent alterations in pathways regulating B-cell development, differentiation and cell cycle progression.1

Mutations in genes encoding epigenetic regulators are common in hematologic malignancies, including ALL. These mutations can occur in genes encoding writers, readers or erasers of the epigenetic marks and can result in a gain or loss of function. Methylation of lysine 27 on histone H3 (H3K27) is commonly dysregulated in both myeloid and lymphoid malignancies. Mutations of EZH2, SUZ12 and EED, members of the Polycomb repressive complex 2 that methylates H3K27, have recently been described in T-cell precursor ALL.2 In addition, loss-of-function mutations of UTX, which functions as a H3K27 demethylase, are found in a number of solid and hematological tumors, including multiple myeloma (MM) and ALL.3 These data suggest that precise regulation of H3K27 methylation is important for normal hematopoiesis.

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References

  1. Inaba H, Greaves M, Mullighan CG . Acute lymphoblastic leukaemia. Lancet 2013; 381: 1943–1955.

    Article  PubMed  Google Scholar 

  2. Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012; 481: 157–163.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genet 2009; 41: 521–523.

    Article  CAS  PubMed  Google Scholar 

  4. Martinez-Garcia E, Popovic R, Min DJ, Sweet SM, Thomas PM, Zamdborg L et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 2011; 117: 211–220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hudlebusch HR, Santoni-Rugiu E, Simon R, Ralfkiaer E, Rossing HH, Johansen JV et al. The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. Clin Cancer Res 2011; 17: 2919–2933.

    Article  CAS  PubMed  Google Scholar 

  6. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 2012; 483: 603–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012; 150: 1107–1120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 2011; 208: 1389–1401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nature Gen 2013; 45: 242–252.

    Article  CAS  Google Scholar 

  10. Beguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M et al. EZH2 is required for germinal center formation and somatic ezh2 mutations promote lymphoid transformation. Cancer Cell 2013; 23: 677–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yuan W, Xu M, Huang C, Liu N, Chen S, Zhu B . H3K36 methylation antagonizes PRC2-mediated H3K27 methylation. J Biol Chemistry 2011; 286: 7983–7989.

    Article  CAS  Google Scholar 

  12. Zheng Y, Sweet SM, Popovic R, Martinez-Garcia E, Tipton JD, Thomas PM et al. Total kinetic analysis reveals how combinatorial methylation patterns are established on lysines 27 and 36 of histone H3. Proc Natl Acad Sci USA 2012; 109: 13549–13554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xiao B, Jing C, Wilson JR, Walker PA, Vasisht N, Kelly G et al. Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature 2003; 421: 652–656.

    Article  CAS  PubMed  Google Scholar 

  14. Ezponda T, Popovic R, Shah MY, Martinez-Garcia E, Zheng Y, Min DJ et al. The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer. Oncogene 2013; 32: 2882–2890.

    Article  CAS  PubMed  Google Scholar 

  15. Qiao Q, Li Y, Chen Z, Wang M, Reinberg D, Xu RM . The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. J Biol Chem 2011; 286: 8361–8368.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Hematology/Oncology, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    J A Oyer, X Huang, T Ezponda, C I Okot-Kotber, J D Licht & R Popovic

  2. Department of Chemistry and Molecular Biosciences, Chemistry of Life Processes, Northwestern University, Evanston, IL, USA

    X Huang, Y Zheng & N L Kelleher

  3. University of Maryland School of Pharmacy, University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA

    J Shim & A D MacKerell Jr

  4. Department of Pathology, Department of Pediatrics, Institute for Cancer Genetics, Columbia University, New York, NY, USA

    Z Carpenter, M Allegretta & A Ferrando

  5. Department of medicine, Human Oncology and Pathogenesis Program, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    J P Patel & R L Levine

  6. Division of Hematology/oncology, Department of Pharmacology, Deparment of Medicine, Weill Cornell Medical College, New York, NY, USA

    A Melnick

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  1. J A Oyer
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Correspondence to J D Licht or R Popovic.

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Oyer, J., Huang, X., Zheng, Y. et al. Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies. Leukemia 28, 198–201 (2014). https://doi.org/10.1038/leu.2013.204

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