Nucleoporin 98-rearranged (NUP98-r) acute myeloid leukemia (AML) is associated with poor outcomes and remains a major therapeutic challenge due to the absence of strategies that directly eliminate NUP98 fusion oncoproteins. Targeted degradation of cancer-driving oncofusions is an attractive approach, but the molecular mechanisms controlling NUP98 oncofusion stability are unknown. Using a CRISPR-Cas9 screen, we identify the E3 ligase Speckle-type POZ protein (SPOP) as a direct regulator of NUP98 fusion oncoprotein stability and a novel tumor suppressor in NUP98-r AML. Loss of SPOP increases NUP98 oncofusion levels and promotes leukemia cell proliferation. Exploiting this specificity, we demonstrate that induced proximity of SPOP and NUP98::lysine-specific demethylase 5A (KDM5A) through a biological proteolysis-targeting chimera (bioPROTAC) induces full clearance of the fusion oncoprotein, driving terminal differentiation and apoptosis of NUP98-r leukemia cells in vitro and in vivo. This study identifies SPOP as a direct regulator of NUP98 oncofusion stability and outlines a strategy to redirect the ubiquitin-proteasome system against oncogenic fusions.