title: Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome.
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.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Garrett W
authors.initials: GW
authors.lastname: Rhyasen
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Bolanos
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.forename: Andres
authors.initials: A
authors.lastname: Jerez
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Carmela
authors.initials: C
authors.lastname: Rigolino
authors.forename: Lesley
authors.initials: L
authors.lastname: Mathews
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Guha
authors.forename: Jonathan
authors.initials: J
authors.lastname: Keller
authors.forename: Craig
authors.initials: C
authors.lastname: Thomas
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
authors.forename: Agostino
authors.initials: A
authors.lastname: Cortelezzi
authors.forename: Esther N
authors.initials: EN
authors.lastname: Oliva
authors.forename: Maria
authors.initials: M
authors.lastname: Cuzzola
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Starczynowski
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D020869:Gene Expression Profiling; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D048029:TNF Receptor-Associated Factor 6; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases