Therapeutic targeting MLL degradation pathways in MLL-rearranged leukemia

Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell 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 leukemia through stabilizing wild-type MLL 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 leukemia and perhaps for other cancers caused by translocations. Overall design: Determination of factors affecting MLL stability using a genome-wide shRNA screen in HEK293 cells. Examination of MLL, MLL chimera, and Super Elongation complex in HEK293 and leukemia cells with and without knockdown, or chemical inhibition, of proteins affecting MLL stability. Control cells such as MLL WT and knockout MEF were used to test MLL antibody specificity specificity