Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Chromosomal translocationsof the mixed-lineage leukemia(MLL) gene with various partner genes result in aggressive leukemiawith dismal outcomes. Despite similar expression at the mRNA level from the wild-typeand chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-typeMLL in response to interleukin-1 signaling. Targeting wild-typeMLL degradation impedes MLL leukemiacell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex. Pharmacologically inhibiting this pathway substantially delays progression, and it improves survival of murine leukemiathrough stabilizing wild-typeMLL protein, which displaces the MLL chimera from some of its target genes and, therefore, relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemiaand perhaps for other cancers caused by translocations.