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Rebecca Olin, MD, MS


Interaction of SMARCA5 and NUP98-NSD1 on Stem Cell Transformation in AML

By: Justine Landin, PhD
Posted: Friday, April 8, 2022

The karyotyping-silent NUP98-NSD1 fusion commonly observed in pediatric acute myeloid leukemia (AML) appears to be highly associated (> 70%) with the activating flt3-itd mutation. According to Angela Bachi, MD, of IFOM-FIRC Institute of Molecular Oncology, Milan, and colleagues, the NUP98-NSD1 fusion is mediated by imitation switch family members involved in the nucleosome remodeling factor complex, such as SMARCA5. The findings of this study were published in the Journal of Experimental Clinical Cancer Research.

“Formation of NUP98-NSD1 phase-separated nuclear condensates is not sufficient for the maintenance of transformed phenotype, which suggests that selective targeting of condensate constituents might represent a new therapeutic strategy for NUP98-NSD1 driven AML,” stated the study investigators.

First, affinity purification with label-free mass spectrometry was utilized to identify interactions between NUP98-NSD1 structural domain deletion on nuclear interactome binding. Additional analyses of primary murine haemopoietic stem cells were used to identify the function of NUP98-NSD1 following genetic and pharmacologic inhibition, as well as the influence on progenitor proliferation, DNA replication, and protein modifications. The phase transition of NUP98-NSD1 was examined via fluorescence recovery following photobleaching and a b-isoxazole assay. 

NUP98-NSD1 binding was found to be highly associated with NUP98 phenylalanine glycine repeat domains, which mediate the formation of phase-separated NUP98-NSD1 nuclear condensates. The remodeling of NUP98-NSD1+ in patient cells appeared to be highly dependent upon interactions between the imitation switch family members involved in the nucleosome remodeling factor complex, such as SMARCA5. NUP98-NSD1+ cells did form an association with SMARCA5 and were associated with NUP98-NSD1/FLT3-ITD formation. However, inhibition of SMARCA5 did not impact NUP98-NSD1 condensates, indicating that functional activity may be more critical than condensate formation in the development of the FLT3-ITD mutation.

The authors concluded: “Our data contain thorough functional information that may be crucial for designing specific inhibitors to be used in NUP98-NSD1 driven AML.”

Disclosure: The study authors reported no conflicts of interest.

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