Restoring chromatin accessibility for MLL reactivates latent tumor suppression-mediated vulnerability to proteasome inhibitors.

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, 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 accessibility and subsequent degradation of MLL, compromises the latent tumor suppressive activity of MLL fusions and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming and can be specifically restored by histone deacetylase (HDAC) inhibitors. Overall design: Examination of differential expressive genes in parental and resistant MLL leukemia cell lines SEM and RS4;11, and drug-resistant cells treated with DMSO or HDAC inhibitors (LBH589 and SAHA).