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Interpretation 20
Tier 1
WHSC1
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
Interpretation

WHSC1 (also known as NSD2 or MMSET) is a H3K36 methyltransferase that converts unmodified H3K36 to the monomethylated and dimethylated forms. NSD2 was recently found to show clonal and subclonal p.E1099K or p.D1125N activating alterations in 15% of t(12;21) ETV6-RUNX1–containing and 15% of TCF3-PBX1 contaning pediatric B-ALLs. The p.E1099K mutation appears to be less prevalent in other types of B-ALL(less than 5%) and both mutations appear to be absent in T-ALL, pediatric AML and adult ALL. In experimental models, increased H3K36 dimethylation and decreased unmodified H3K36 was associated with the NSD2 p.E1099K variant or the t(4;14) translocation( which leads to overexpression of NSD2). Overexpression of NSD2 in t(4;14)-positive multiple myeloma (MM) is also associated with globally increased levels of H3K36 dimethylation and decreased K27 trimethylation. NSD2 is considered to be a potential therapeutic target for a subset of cases of pediatric B-ALL.

Citations
  1. Jaffe JD, et al. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat Genet 2013;45(11):1386-91
  2. Oyer JA, et al. Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies. Leukemia 2014;28(1):198-201
Last updated: 2016-06-04 21:46:58 UTC
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When using PMKB, please cite: Huang et al., JAMIA 2017


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