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. 2014 Jan;28(1):198-201.
doi: 10.1038/leu.2013.204. Epub 2013 Jul 4.

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

J A Oyer  1 , X Huang  2 , Y Zheng  3 , J Shim  4 , T Ezponda  1 , Z Carpenter  5 , M Allegretta  5 , C I Okot-Kotber  1 , J P Patel  6 , A Melnick  7 , R L Levine  6 , A Ferrando  5 , A D Mackerell Jr  4 , N L Kelleher  3 , J D Licht  1 , R Popovic  1
Affiliations

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

J A Oyer et al. Leukemia. 2014 Jan.
No abstract available

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Recurrent E1099K mutation of MMSET in cancer. (a) Diagram of the MMSET protein. E1099K mutation within the SET domain is denoted by a star. (b) Table summarizing previously published studies identifying MMSET E1099K mutation in various tumors. (c) Sequence chromatogram for the B-precursor ALL patient carrying an E1099K MMSET mutation. The presence of both A and G peaks (orange highlight) indicates heterozygous mutation at this position. (d) Expression of MMSET mRNA across various cancer cell lines. The highest level of expression can be seen in lymphoid cells. The figure has been adapted from the Broad Cancer Cell Line Encyclopedia.
Figure 2
Figure 2
E1099K mutation of MMSET is associated with altered global histone methylation and gene expression. (a) Western blots using nuclear extracts from MM (left) and ALL (right) cell lines expressing the wild-type or E1099K mutant MMSET. The presence of E1099K mutation correlates with enhanced H3K36 dimethylation and concomitant global decrease in H3K27 trimethylation. Total H4 is used as a loading control. (b) Quantitative RT-PCR for MMSET in MM and ALL cell lines. KMS11 cells contain t(4;14) translocation and thus express elevated levels of MMSET, whereas the rest of the cell lines express lower levels of MMSET, independently of the presence of the mutation. (c) Mass spectrometry analysis of histones from MM and ALL cell lines expressing the wild type or E1099K mutant MMSET. The analysis was performed as described previously. Mutant cells have increased methylation of lysine 36 and decreased methylation of lysine 27. (d) Proposed substrate-binding site of MMSET. The αB and β-sheet 5 of SET domain are represented in gray and post-SET loop in green. Side chains of residues in αB and β-sheet 5 are shown in licorice representation and E1099 and S-adenosyl-L-methionine (SAM) are shown in atom colored vdW representation. A homology model of MMSET (NSD2) was developed based on NSD1 crystal structure (3OOI.pdb) using the program Modeller. The SET domain of NSD1 shares 75.9% sequence identity and 88.8% positive conservation with the MMSET SET domain without any gaps. As in the 3D structure of NSD1, the site that binds the C-terminal side of the H3 peptide in the MMSET model is in the cleft between SET and post-SET loops and contains E1099. (e) Heat map representing the most highly differentially expressed genes in MMSET wild-type (n = 7) and E1099K mutant (n = 5) ALL cell lines. The data and the figure were extracted from the Broad Cancer Cell Line Encyclopedia.
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