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Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models

Clarisse Thiollier 1 Cécile Lopez 1 Bastien Gerby 2 Cathy Ignacimouttou 1 Sandrine Poglio 2 Yannis Duffourd 1 Justine Guégan 1 Paola Rivera-Munoz 1 Olivier Bluteau 1 Vinciane Mabialah 1 M’boyba Diop 1 Qiang Wen Arnaud Petit 3 Anne-Laure Bauchet 4 Dirk Reinhardt 5 Beat Bornhauser 6 Daniel Gautheret 1 Yann Lécluse 1 Judith Landman-Parker 7, 3 Isabelle Radford William Vainchenker 1 Nicole Dastugue 8, 9 Stephane de Botton 10 Philippe Dessen 1 Jean-Pierre Bourquin 6 John Crispino Paola Ballerini 11, 3 Olivier Bernard 12 Francoise Pflumio 2 Thomas Mercher 13, 1
1 IGR - Institut Gustave Roussy
2 IRCM - Institut de Radiobiologie Cellulaire et Moléculaire
3 AP-HP - Hôpital Armand Trousseau [AP-HP]
4 MIRCEN - Service MIRCEN
5 MHH - Hannover Medical School [Hannover]
6 UZH - University of Zürich [Zürich]
7 UPMC - Université Pierre et Marie Curie - Paris 6
8 Laboratoire d'Hématologie
9 Hôpital Purpan [Toulouse]
10 U1170 Inserm - Hématopoïèse normale et pathologique
11 Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau]
12 Images et Modèles
CREATIS - Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé
13 U985 - Génétique des tumeurs
Abstract : Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non-Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors.
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IGR | UNIV-PARIS | USPC | JACOB | CEA-DRF | INSA-GROUPE | SORBONNE-UNIVERSITE | MIRCEN | FNCLCC | CREATIS | UNIV-ST-ETIENNE | CEA | UNIV-PARIS5 | UPMC | HCL | CNRS | UNIV-LYON1 | INSA-LYON | UDL | SU-MEDECINE | SU-TI

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Clarisse Thiollier, Cécile Lopez, Bastien Gerby, Cathy Ignacimouttou, Sandrine Poglio, et al.. Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models. Journal of Experimental Medicine, Rockefeller University Press, 2012, 209 (11), pp.2017-2031. ⟨10.1084/jem.20121343⟩. ⟨hal-02353632⟩

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