1. Targeting IRAK1 as a Therapeutic Approach for Myelodysplastic Syndrome.
- Author
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Rhyasen, Garrett?W., Bolanos, Lyndsey, Fang, Jing, Jerez, Andres, Wunderlich, Mark, Rigolino, Carmela, Mathews, Lesley, Ferrer, 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., and Starczynowski, Daniel?T.
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MYELODYSPLASTIC syndromes treatment , *INTERLEUKIN-1 receptors , *HEMATOPOIETIC stem cells , *KINASE inhibitors , *TARGETED drug delivery , *PROGENITOR cells , *GENE expression , *IMMUNOREGULATION - Abstract
Summary: 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. [Copyright &y& Elsevier]
- Published
- 2013
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