Nizp1 is a specific NUP98-NSD1 functional interactor that regulates NUP98-NSD1-dependent oncogenic programs

: NSD1, NSD2 and NSD3 proteins constitute a family of histone 3 lysine 36 (H3K36) methyltransferases with similar domain architecture, but diversified activities, in part, dependent on their non-enzymatic domains. These domains, despite their high sequence identity, recruit the hosting proteins to different chromatin regions through the recognition of diverse epigenetic marks and/or associations to distinct interactors. In this sense, the PHDvC5HCH finger tandem domain represents a paradigmatic example of functional divergence within the NSD family. In this work, we prove and give a structural rationale for the uniqueness of the PHDvC5HCH domain of NSD1 in recognizing the C2HR Zinc finger domain of Nizp1 (NSD1 interacting Zn finger protein). Importantly, we show that, in a leukaemogenic context, Nizp1 is pivotal in driving the unscheduled expression of HoxA genes and of genes involved in the type I IFN pathway, triggered by the expression of the fusion protein NUP98-NSD1. These data provide the first insight into the pathophysiological relevance of the Nizp1-NSD1 functional association. Targeting of this interaction might open new therapeutic windows to inhibit the NUP98-NSD1 oncogenic properties.