// Charles Dussiau 1, * , Amélie Trinquand 1, * , Ludovic Lhermitte 1 , Mehdi Latiri 1 , Mathieu Simonin 1 , Agata Cieslak 1 , Nawel Bedjaoui 1 , Patrick Villarèse 1 , Els Verhoeyen 2, 3 , Hervé Dombret 4 , Norbert Ifrah 5 , Elizabeth Macintyre 1 , Vahid Asnafi 1 1 Université 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 2 CIRI, EVIR Team, INSERM, U1111, CNRS, UMR5308, Université de Lyon-1, ENS de Lyon, Lyon, France 3 INSERM, U1065, C3M, Equipe "Contrôle Métabolique des Morts Cellulaires", Nice, France 4 University Paris 7, Hôpital Saint-Louis, AP-HP, Department of Hematology and Institut Universitaire d'Hématologie, EA, Paris, France 5 PRES 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.
<div>Abstract<p>Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein–Barr virus (EBV)–related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, <i>HLA-B</i>, <i>HLA-C</i>, <i>ROBO1</i>, <i>CD58</i>, <i>POT1</i>, and <i>MAP2K1</i>. Among them, <i>CD274</i> (24%) was the most frequently altered, followed by <i>TP53</i> (20%), <i>CDKN2A</i> (19%), <i>ARID1A</i> (15%), <i>HLA-A</i> (15%), <i>BCOR</i> (14%), and <i>MSN</i> (14%). Chromosome X losses were the most common arm-level CNAs in females (∼40%), and alterations of four X-linked driver genes (<i>MSN</i>, <i>BCOR</i>, <i>DDX3X</i>, and <i>KDM6A</i>) were more frequent in males and females harboring chromosome X losses. Among X-linked drivers, <i>MSN</i> was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines showed that <i>MSN</i> disruption promoted cell proliferation and NF-κB activation. Moreover, <i>MSN</i> inactivation increased sensitivity to NF-κB inhibition <i>in vitro</i> and <i>in vivo</i>. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, nonnegative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognoses irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL.</p><p><b>Significance:</b> Integrative genetic analyses and functional studies in extranodal NK/T-cell lymphoma identify frequent disruptions of X-linked drivers, reveal prognostic molecular subgroups, and uncover recurrent <i>MSN</i> alterations that confer sensitivity to NF-κB inhibition.</p></div>
