Targeting IRAK1 in T-cell acute lymphoblastic leukemia
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Charles Dussiau1,*, Amélie Trinquand1,*, Ludovic Lhermitte1, Mehdi Latiri1, Mathieu Simonin1, Agata Cieslak1, Nawel Bedjaoui1, Patrick Villarèse1, Els Verhoeyen2,3, Hervé Dombret4, Norbert Ifrah5, Elizabeth Macintyre1, Vahid Asnafi1
1Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker-Enfants Malades, Paris, France
2CIRI, EVIR Team, INSERM, U1111, CNRS, UMR5308, Université de Lyon-1, ENS de Lyon, Lyon, France
3INSERM, U1065, C3M, Equipe “Contrôle Métabolique des Morts Cellulaires”, Nice, France
4University Paris 7, Hôpital Saint-Louis, AP-HP, Department of Hematology and Institut Universitaire d’Hématologie, EA, Paris, France
5PRES LUNAM, CHU Angers Service des Maladies du Sang et INSERM U 892, Angers, France
*These authors have contributed equally to this work
Vahid Asnafi, e-mail: email@example.com
Keywords: T-ALL, IRAK1, kinases, therapeutic target
Received: December 12, 2014 Accepted: May 20, 2015 Published: June 01, 2015
T-cell acute lymphoblastic leukemia (T-ALL) represents expansion of cells arrested at specific stages of thymic development with the underlying genetic abnormality often determining the stage of maturation arrest. Although their outcome has been improved with current therapy, survival rates remain only around 50% at 5 years and patients may therefore benefit from specific targeted therapy. Interleukin receptor associated kinase 1 (IRAK1) is a ubiquitously expressed serine/threonine kinase that mediates signaling downstream to Toll-like (TLR) and Interleukin-1 Receptors (IL1R). Our data demonstrated that IRAK1 is overexpressed in all subtypes of T-ALL, compared to normal human thymic subpopulations, and is functional in T-ALL cell lines. Genetic knock-down of IRAK1 led to apoptosis, cell cycle disruption, diminished proliferation and reversal of corticosteroid resistance in T-ALL cell lines. However, pharmacological inhibition of IRAK1 using a small molecule inhibitor (IRAK1/4-Inh) only partially reproduced the results of the genetic knock-down. Altogether, our data suggest that IRAK1 is a candidate therapeutic target in T-ALL and highlight the requirement of next generation IRAK1 inhibitors.
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