Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome.
Cancer Cell, 2013/7/08;24(1):90-104.
Rhyasen GW[1], Bolanos L, Fang J, Jerez A, Wunderlich M, Rigolino C, Mathews L, Ferrer M, Southall N, Guha R, Keller J, Thomas C, Beverly LJ, Cortelezzi A, Oliva EN, Cuzzola M, Maciejewski JP, Mulloy JC, Starczynowski DT
Affiliations
PMID: 23845443
Impact factor: 38.585
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.
MeSH terms
Animals; Apoptosis; Cell Line; Gene Expression Profiling; Humans; Interleukin-1 Receptor-Associated Kinases; Mice; Myelodysplastic Syndromes; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; TNF Receptor-Associated Factor 6; Xenograft Model Antitumor Assays
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