Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome.

Therapeutic Approaches

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.

Authors

Rhyasen, Garrett W; Bolanos, Lyndsey; Fang, Jing; Jerez, Andres; Wunderlich, Mark; Rigolino, Carmela; Mathews, Lesley; Ferrer-Alegre, Marc; Southall, Noel; Guha, Rajarshi; Keller, Jonathan; Thomas, Craig; Beverly, Levi J; Cortelezzi, Agostino; Oliva, Esther N; Cuzzola, Maria; Maciejewski, Jaroslaw P; Mulloy, James C; Starczynowski, Daniel T;

Keywords

  • 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

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