Editors' ChoiceCancer

Suppressing oncogenic transcription with a little healthy competition

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Science Translational Medicine  25 Jan 2017:
Vol. 9, Issue 374, eaal5000
DOI: 10.1126/scitranslmed.aal5000

Abstract

Therapeutic strategies that stabilize wild-type MLL proteins have selective activity in MLL-rearranged leukemias.

Mixed-lineage leukemias (MLLs), which include subsets of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), are aggressive malignancies characterized by poor clinical outcomes. MLLs are driven by chromosomal translocations involving one allele of the MLL gene, which encodes a transcriptional coactivator with histone methyltransferase activity, and a variety of partner genes. The deregulation of target genes by MLL chimeras drives malignant progression in these leukemias by accelerating growth and blocking differentiation.

In a recent report, Liang and a team of researchers observed that wild-type MLL (WT-MLL) proteins are much less abundant than MLL chimeras in MLL-rearranged cells, an effect likely owing to differences in protein stability given that mRNA levels of the two species are comparable. They therefore hypothesized that WT-MLL could be stabilized by targeting the pathways responsible for its degradation, and that by doing so, it may be possible to competitively displace MLL chimeras from chromatin, blocking their oncogenic activity. Using both biochemical and functional genomic approaches, they discovered that the interleukin-1 (IL-1) pathway promotes the degradation of WT-MLL through its interaction with the ubiquitin-conjugating enzyme UBE2O. Blocking this pathway using inhibitors of interleukin-1 receptor–associated kinase 4 (IRAK4) or knockdown of UBE2O resulted in stabilization of WT-MLL protein, displacement of MLL chimeras from target genes, selective killing of MLL-rearranged leukemia cells in vitro, and delayed disease progression in mouse models.

This study demonstrates that the approach of stabilizing WT-MLL through pharmacological inhibition of a degradation pathway may be an exciting translational strategy for these tumors. This work also adds to a growing body of potentially powerful therapeutic strategies for MLL-rearranged leukemias, which also includes small molecules that disrupt the Menin-MLL interaction, inhibitors of bromodomain-containing protein 4 (BRD4) chromatin binding, and inhibitors of the disruptor of telomeric silencing 1-like (DOT1L) methyltransferase. Last, and provocatively, this study also suggests that stabilization of wild-type proteins may be a generalizable strategy for treating cancers driven by genomic translocations.

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