MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.