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

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-Parker, Isabelle RadfordWilliam Vainchenker, Nicole Dastugue, Stéphane de Botton, Philippe Dessen, Jean Pierre Bourquin, John D. Crispino, Paola Ballerini, Olivier A. Bernard, Françoise Pflumio, Thomas Mercher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2017-2031
Number of pages15
JournalJournal of Experimental Medicine
Issue number11
StatePublished - Oct 2012

ASJC Scopus subject areas

  • Medicine(all)


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