Oncotarget

Research Papers:

Targeting IRAK1 in T-cell acute lymphoblastic leukemia

Charles Dussiau _, Amélie Trinquand, Ludovic Lhermitte, Mehdi Latiri, Mathieu Simonin, Agata Cieslak, Nawel Bedjaoui, Patrick Villarèse, Els Verhoeyen, Hervé Dombret, Norbert Ifrah, Elizabeth Macintyre and Vahid Asnafi

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Oncotarget. 2015; 6:18956-18965. https://doi.org/10.18632/oncotarget.4150

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Abstract

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

Correspondence to:

Vahid Asnafi, e-mail: vahid.asnafi@nck.aphp.fr

Keywords: T-ALL, IRAK1, kinases, therapeutic target

Received: December 12, 2014     Accepted: May 20, 2015     Published: June 01, 2015

ABSTRACT

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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