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

NUP98–NSD1 fusion mRNA is the transcript resulting from the cryptic chromosomal translocation t(5;11)(q35;p15.5), which is a hallmark of a high-risk subset of acute myeloid leukemia (AML), particularly in pediatric and cytogenetically normal patients. The fusion joins the N-terminal portion of Nucleoporin 98 (NUP98) with the C-terminal SET domain of the Nuclear receptor binding SET domain protein 1 (NSD1), creating an oncoprotein that functions as a potent transcriptional activator. This fusion protein binds to the promoters of homeobox genes, such as HOXA9 and MEIS1, maintaining them in an active chromatin state and preventing the differentiation of hematopoietic progenitor cells. Therapeutically, the NUP98–NSD1 fusion mRNA is a target for direct inhibition via siRNA-loaded lipid nanoparticles, which have shown efficacy in prolonging survival in preclinical models. Additionally, the leukemic cells driven by this fusion exhibit dependencies on downstream effectors like CDK6 and BCL-2, making them sensitive to inhibitors such as palbociclib, dasatinib, and navitoclax. The presence of this fusion is often associated with co-occurring mutations like FLT3-ITD and NRAS, which further contribute to its aggressive clinical course and resistance to standard topoisomerase II inhibitors. Targeting the Menin-MLL1 complex has also emerged as a promising strategy to disrupt the oncogenic transcriptional program initiated by the NUP98–NSD1 fusion.

Other names

t(5;11)(q35;p15.5) fusionNUP98-NSD1 chimeric transcriptNUP98-NSD1 oncoproteinNUP98/NSD1

Direct targeting of the fusion mRNA via RNA interference (siRNA) or pharmacological inhibition of downstream effectors and co-factors such as CDK6, BCL-2, and the Menin-MLL1 complex.