Therapeutic Targeting of Childhood Leukemia by Pharmacological Inhibition of Proteolytic Cleavage of MLL1
Background: MLL1, which is found in a large number of translocations associated with childhood leukemia, is post transcriptionally processed and cleaved by Threonine aspartase 1 (taspase1). But the biological significance of the cleavage of MLL1 by taspase1 in mammalian cells remains debated due to the different murine models used in previous studies. My preliminary studies in Shilatifard's laboratory demonstrated that taspase1 cleavage destabilized the MLL1 protein and primed the protein to its degradation pathways without affecting its nuclear localization and activation. I have further demonstrated that the phosphorylation on MLL1 flanking the taspase1 cleavage site is a crucial pre-requisite for taspase1-mediated cleavage, thus providing us with a molecular means regulating the stability of MLL1. Our lab's recent study published in Cell in 2017 demonstrated that MLL1 stability controls a precise process that determines its activity and occupancy at the target genes.
Project Goal: The functions of MLL1 in leukemic pathogenesis are substantially affected if the MLL degradation machinery is altered. Therefore, I will take advantage of my findings of the role of taspase1 in the regulation of MLL1 stability through the biological function of MLL1 phosphorylation, coupled with taspase1 cleavage to develop new therapeutic approaches for the treatment of MLL translocation-based leukemia and in tumors with taspase1 overexpression.
Project Update 2022: We have demonstrated that taspase1-dependent cleavage of MLL1 results in the destabilization of full-length MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version and this stabilization of the uncleaved MLL1 can result in the displacement of MLL-chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL-chimeras from chromatin. Our study provides insights into the direct regulation of the stability of MLL1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive MLL leukemia using CKII inhibitors. In contrast to the unique C-terminus regulation of MLL1 by taspase1, we demonstrated that the N-terminus MLL1 binding factors menin and LEDGF cooperate to contribute to the chromatin recruitment of MLL1, suggesting co-targeting menin and LEDGF will be an efficient alternative approach for the childhood MLL-r leukemia, which will be explored in our ongoing study.
