Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by caspase-8 and upregulation of p27, respectively. Furthermore, proteasome inhibition conferred preliminary benefit to patients with MLL-AF4 leukemia. Hence, feasible strategies to treat cancer-type and oncogene-specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions. •MLL fusion renders cancer type-specific hypersensitivity to proteasome inhibitors•Proteasome inhibitors engage extrinsic cell death pathway in pro-B MLL leukemia cells•Bortezomib activates p27 through a pro-B leukemia-specific PAX5/MLL-fusion complex•In vivo efficacy against pro-B MLL leukemia was observed with proteasome inhibitors Liu et al. show that high levels of MLL fusion proteins selectively suppress pro-B, but not myeloid MLL leukemia cells. In addition, clinical proteasome inhibitors kill pro-B MLL leukemia cells by inducing MLL fusion protein accumulation and show a promising clinical benefit in patients with pro-B MLL leukemia.