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

• DOI: 10.1084/jem.20121343
• Publication Date: 2012-10-09T05:27:27Z
• Authors: Clarisse Thiollier; Cécile K. Lopez; Bastien Gerby; Cathy Ignacimouttou; Sandrine Poglio; Yannis Duffourd; Justine Guégan; Paola Rivera-Munoz; Olivier Bluteau; Vinciane Mabialah; M’Boyba Diop; Qiang Wen; Arnaud Petit; Anne-Laure Bauchet; Dirk Reinhardt; Beat Bornhauser; Daniel Gautheret; Yann Lecluse; Judith Landman-Pa...; Isabelle Radford; William Vainchenker; Nicole Dastugue; Stéphane de Botton; Philippe Dessen; Jean-Pierre Bourquin; John D. Crispino; Paola Ballerini; Olivier A. Bernard; Françoise Pflumio; Thomas Mercher
• Keywords: Acute megakaryoblastic leukemia; GATA1; Trisomy

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 past years, including t(1;22)(p13;q13) trisomy 21 GATA1 mutations. However, majority patients do not present known mutations, limited access to primary patient leukemic cells impedes efficient development novel therapeutic strategies. In this study, using xenotransplantation approach, we modeled human pediatric AMKL immunodeficient mice. Analysis high-throughput RNA sequencing identified recurrent fusion genes defining new subgroups. One subgroup presented MLL or NUP98 leading up-regulation HOX A cluster genes. CBFA2T3-GLIS2 gene resulting from cryptic inversion chromosome 16 was another 31% non-Down syndrome strongly signature Hedgehog pathway activation. These data provide useful markers for diagnosis follow up patients. Finally, show that xenograft models constitute relevant vivo preclinical screening platform validate efficacy therapies such as Aurora kinase inhibitors.