Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome

Cancer Cell. 2013 Jul 8;24(1):90-104. doi: 10.1016/j.ccr.2013.05.006.

Abstract

Myelodysplastic syndromes (MDSs) arise from a defective hematopoietic stem/progenitor cell. Consequently, there is an urgent need to develop targeted therapies capable of eliminating the MDS-initiating clones. We identified that IRAK1, an immune-modulating kinase, is overexpressed and hyperactivated in MDSs. MDS clones treated with a small molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-κB inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is detrimental to MDS cells, while sparing normal CD34(+) cells. Based on an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that cotreatment more effectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDSs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line
  • Gene Expression Profiling
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / physiology
  • Mice
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / pathology
  • NF-kappa B / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • TNF Receptor-Associated Factor 6 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • TNF Receptor-Associated Factor 6
  • IRAK1 protein, human
  • Interleukin-1 Receptor-Associated Kinases