Nucleoporin 98-Nuclear receptor binding SET domain protein 1 fusion protein (NUP98-NSD1) (NUP98-NSD1)

The Nucleoporin 98-Nuclear receptor binding SET domain protein 1 (NUP98-NSD1) fusion protein is a chimeric oncoprotein resulting from the t(5;11)(q35;p15.5) chromosomal translocation, most frequently identified in pediatric and young adult acute myeloid leukemia (AML) (Shiba et al., 2013, Blood). This fusion protein consists of the N-terminal phenylalanine-glycine (GLFG) repeats of NUP98 and the C-terminal SET domain of NSD1, which possesses histone H3 lysine 36 (H3K36) methyltransferase activity (Wang et al., 2007, Nature Genetics). NUP98-NSD1 functions as an aberrant epigenetic regulator that binds to and maintains the expression of critical leukemogenic genes, including the HOXA and HOXB clusters and MEIS1, thereby arresting myeloid differentiation and promoting self-renewal (McNeer et al., 2018, Nature Genetics). Clinically, the presence of NUP98-NSD1 is a marker of poor prognosis, characterized by low remission rates and high risk of relapse (Ostronoff et al., 2014, Blood). While traditionally difficult to target directly, recent research has demonstrated that NUP98-NSD1-driven leukemias are highly sensitive to Menin-KMT2A (MLL) inhibitors, such as revumenib and ziftomenib (Issa et al., 2023, Nature). These drugs disrupt the essential interaction between Menin and the KMT2A complex, which is required for the fusion protein's transcriptional activity and survival of the leukemic cells (Heikamp et al., 2022, Blood). Therapeutic challenges include the development of resistance mutations in the Menin protein and the management of differentiation syndrome during treatment (Perner et al., 2023, Nature).

Other names

t(5;11)(q35;p15.5) fusion proteinNUP98-NSD1 chimeric proteinNUP98/NSD1

Disruption of the Menin-KMT2A (MLL) interaction to suppress the expression of HOX cluster genes and MEIS1, which are essential for the maintenance of the leukemic state (Issa et al., 2023, Nature).