Stabilization of Wild-Type MLL Displaces Oncogenic MLL Fusion Proteins

Chromosomal translocations involving the mixed-lineage leukemia (MLL) gene, which encodes an enzyme that catalyzes the methylation of histone H3 lysine 4, are associated with a poor prognosis in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and more effective targeted therapies are needed. Liang and colleagues found that, despite similar mRNA expression, the wild-type MLL protein was more abundant than the chimeric MLL fusion protein in leukemia cells, suggesting the possibility that stabilizing wild-type MLL might displace chimeric MLL fusion proteins from chromatin. The E2/E3 ubiquitin ligase UBE2O was found to interact with the C-terminus of MLL, which is lacking in the MLL chimeras, thereby promoting degradation of wild-type MLL, but not the chimeric fusion proteins. Mechanistically, IL1 signaling promoted phosphorylation of UBE2O by the IRAK4 kinase, which enhanced the MLL–UBE2O interaction and promoted degradation of wild-type MLL. Thus, IRAK inhibition reduced the MLL–UBE2O interaction and increased MLL stability and occupancy at target genes, and reduced occupancy of chimeric MLL at a subset of target genes including super elongation complex genes. Further, an IRAK4 inhibitor reduced the proliferation and viability of patient-derived leukemia cell lines harboring MLL fusions, but not of cells without MLL rearrangements or of an MLL-rearranged cell line in which the wild-type MLL allele was also deleted, indicating that the wild-type MLL allele is required for enhanced sensitivity of MLL-rearranged cells to IRAK inhibition. Moreover, IRAK inhibition improved survival and slowed disease progression in a mouse model of MLL-AF9 leukemia, highlighting IRAK as a potential therapeutic target in MLL-rearranged leukemia. Altogether, these results suggest that stabilizing wild-type MLL may have therapeutic potential in patients with MLL-rearranged leukemia, and these findings may extend to tumors driven by other fusion proteins.

Liang K, Volk AG, Haug JS, Marshall SA, Woodfin AR, Bartom ET, et al. Therapeutic targeting of MLL degradation pathways in MLL-rearranged leukemia. Cell 2017;168:59–72.e13.

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