Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Kaiwei Liang, Andrew G. Volk, J. S. Haug, Stacy A. Marshall, Ashley R. Woodfin, Elizabeth T. Bartom, Joshua M. Gilmore, Laurence Florens, Michael P. Washburn, Kelly D. Sullivan, Joaquin M. Espinosa, Joseph Cannova, Jiwang Zhang, Edwin R. Smith, John D. Crispino, Ali Shilatifard*

*Corresponding author for this work

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)59-72.e13
JournalCell
Volume168
Issue number1-2
DOIs
StatePublished - Jan 12 2017

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Keywords

  • IRAK1
  • IRAK4
  • MLL
  • MLL chimera
  • SEC
  • UBE2O
  • interleukin-1
  • mixed-lineage leukemia
  • super elongation complex
  • wild-type MLL

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Liang, K., Volk, A. G., Haug, J. S., Marshall, S. A., Woodfin, A. R., Bartom, E. T., Gilmore, J. M., Florens, L., Washburn, M. P., Sullivan, K. D., Espinosa, J. M., Cannova, J., Zhang, J., Smith, E. R., Crispino, J. D., & Shilatifard, A. (2017). Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia. Cell, 168(1-2), 59-72.e13. https://doi.org/10.1016/j.cell.2016.12.011