Abstract A39: Nuclear SET domain (NSD) protein lysine methyltransferases (KMT) are higher expressed in acute myeloid leukemia

The nuclear SET domain (NSD) protein lysine methyltransferases (KMT) family is composed of three members, NSD1/KMT3B, NSD2/WHSC1/MMSET, and NSD3/WHSC1L1, which regulate gene expression through methylation of lysine 36 of histone H3 (H3K36). NSD2 overexpression was reported in multiple myeloma with t(4;14)/IgH-MMSET. NSDs gene expression profile is unknown in acute leukemias; however, NSD1 and NSD3 were described to be fused with the nucleoporin 98 gene (NUP98) in rare AML and myelodysplastic syndrome cases and both fusion proteins were associated with poor prognosis. The aims of the present study were to characterize the expression of NSD-KMTs in patients with AML and healthy controls, to determine if this expression is associated with specific genetic abnormalities and/or with treatment outcome. Bone marrow aspirates from four healthy donors and 94 AML patients (50♀, 44♂) at diagnosis were included in the study. Our cohort included 10 patients with acute promyelocytic leukemia (APL), 8 with core binding factor (CBF) leukemias [6 with t(8;21) and 4 with inv(16)], and 74 patients with non-APL non-CBF AML. NSD family gene expression was evaluated by qPCR using the comparative Ct method for analysis. A higher expression of the NSD1 gene was observed in AML cells compared to normal bone marrow (BM) samples (median [range] = 3.8835 [0.6804-11.5598] vs. 1.003 [0.7956-1.265], p=0.0243). Similarly, the expression of NSD3 was higher in AML only for the comparison between healthy BM and CBF-AML groups (median [range] = 1.070 [0.6360-1.410] vs. 2.719 [1.238-8.830], p=0.0265). No significant differences were detected in the analysis of NSD2 expression. The association between expression levels of NSD-KMT with age, gender, prognosis (favorable vs. unfavorable), presence or absence of FLT3-ITD and NPM1 mutations, and presence or absence of karyotype abnormalities was evaluated. With the exception of NSD3 and presence/absence of karyotype abnormalities, NSD-KMT gene expression levels were higher in AML subgroups when compared to healthy donors, in all above parameters. NSD2 was more expressed in AML when compared to NSD1/NSD2 groups. NPM1 mutations and FLT3 internal tandem duplications (FLT3-ITD) were detected in 19.1% (18/94) of the patients with AML. NSD1/NSD3 were more expressed in FLT3-ITD mutant vs. FLT3 wild-type group. In addition, NSD2 was frequently more observed in patients aged 65 or older. Next, patients were stratified into two groups according to the median