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.